Antibiotics-2021-Looking Back To Amycolatopsis

antibiotics
Review
Looking Back to Amycolatopsis: History of the Antibiotic
Discovery and Future Prospects
Olga V. Kisil , Tatiana A. Efimenko * and Olga V. Efremenkova
Gause Institute of New Antibiotics, 119021 Moscow, Russia; [email protected] (O.V.K.); [email protected] (O.V.E.)
* Correspondence: [email protected]
Abstract: The emergence of antibiotic-resistant pathogenic bacteria in recent decades leads us to an

urgent need for the development of new antibacterial agents. The species of the genus Amycolatopsis
are known as producers of secondary metabolites that are used in medicine and agriculture. The
complete genome sequences of the Amycolatopsis demonstrate a wide variety of biosynthetic gene
clusters, which highlights the potential ability of actinomycetes of this genus to produce new antibi-
otics. In this review, we summarize information about antibiotics produced by Amycolatopsis species.
This knowledge demonstrates the prospects for further study of this genus as an enormous source
of antibiotics.
Keywords: antibiotics; antimicrobial compounds; genus Amycolatopsis; glycopeptide antibiotics;

polyene antibiotics; rifamycins

Citation: Kisil, O.V.; Efimenko, T.A.;

Efremenkova, O.V. Looking Back to 1. Introduction
Amycolatopsis: History of the
The science of antibiotics was formed in the twentieth century. About a hundred
Antibiotic Discovery and Future
years ago, Alexander Fleming described the suppression of bacterial growth in an agar
Prospects. Antibiotics 2021, 10, 1254.
https://doi.org/10.3390/
medium under the action of a certain substance released into the environment by a fungus
antibiotics10101254
colony growing nearby. This fungus was Penicillium chrysogenum, and the first discovered
antibiotic was called penicillin. In the 1940s, an active search for natural antimicrobial
Academic Editors: compounds among representatives of various groups of organisms began. In 1952, Zelman
Jesus Simal-Gandara, Lillian Barros Waxman introduced the term “antibiotics”. By the 1960s, all the major groups of currently
and Miguel A. Prieto Lage known antibiotics had been discovered. Unlike the previous half-century period, during
which all the main classes of antibiotics were described, in the twenty-first century the
Received: 15 August 2021 effectiveness of the search for new natural antibiotics has significantly decreased. An
Accepted: 12 October 2021 additional problem was the emergence of antibiotic-resistant microorganisms. The emer-
Published: 15 October 2021 gence of antibiotic resistance was a natural biological response to antimicrobial drug use,
which created selective pressure that promoted the selection, survival and reproduction
Publisher’s Note: MDPI stays neutral of microorganism-resistant strains. The spread of antibiotic-resistant microorganisms re-
with regard to jurisdictional claims in duces the effectiveness of prevention and treatment of infectious and parasitic diseases in
published maps and institutional affil- humans, animals and plants, leads to an increase in the severity and duration of these dis-
iations. eases, an increase in mortality among the population, and the death of animals and plants.
The decline in the effectiveness of existing clinically important antibiotics has motivated
researchers to search for new molecules with antimicrobial properties to overcome antimi-
crobial resistance. The phylum Actinobacteria represents one of the most diverse groups of
Copyright: © 2021 by the authors. microorganisms recognized within the domain Bacteria. Among the phylum Actinobacteria,
Licensee MDPI, Basel, Switzerland. the genus Streptomyces is the source of 70–80% of all secondary metabolites; in addition,
This article is an open access article the important producers of antibiotics are the Amycolatopsis, Actinoplanes, Micromonospora
distributed under the terms and and Saccharopolyspora genera [1]. In our review we focus on antibiotics produced by genus
conditions of the Creative Commons Amycolatopsis, including the history of their discovery, the emergence of resistance, and the
Attribution (CC BY) license (https:// current state of the new drug discovery problem.
creativecommons.org/licenses/by/
4.0/).
Antibiotics 2021, 10, 1254. https://doi.org/10.3390/antibiotics10101254 https://www.mdpi.com/journal/antibiotics

Antibiotics 2021, 10, 1254 2 of 25
2. The History and Genomic Analysis of Amycolatopsis

The history of the genus Amycolatopsis is closely connected with the history of the
discovery of antibiotics. The genus Amycolatopsis was previously widely used as one of the
most effective sources of producers of secondary metabolites with antibacterial, antifungal,
or antiviral properties and continues to be the focus of attention when searching for new
drugs today [2–4]. In the golden era of antibiotics in the 1950s, vancomycin and related
glycopeptides (Amycolatopsis orientalis) and rifamycin (Amycolatopsis mediterranei) were
discovered. In addition to antibiotic production, the importance of Amycolatopsis strains
in industry and ecology, namely bioremediation (heavy metal immobilization, herbicide,
and polymer biodegradation) and bioconversion (wuxistatin and vanillin production) was
reported [2,5,6]. Some members of the genus Amycolatopsis were initially misidentified as
Streptomyces or Nocardia. Only in 1986 did Lechevalier finally recognize Amycolatopsis as a
unique genus of nocardioform actinomycetes, that lack mycolic acids but contain meso-
diaminopimelic acid, arabinose, and galactose in the peptidoglycan of the cell wall [7].
A. orientalis was the first recorded species of this genus. The Amycolatopsis strains are
widespread and are isolated mainly from soil [8]. In addition, the Amycolatopsis strains
have been isolated from medieval alum slate mine [9], lichen [10], ocean sediment [11],
vegetable matter [12], insects [13,14], clinical sources [15,16], and equine placentas [17].
Only four Amycolatopsis species are known to have pathogenic properties [15–17].
As of 2021, the number of officially accepted and published species of the genus
Amycolatopsis is 83 (Figure 1) [18]. The genome sequences of 120 Amycolatopsis strains have
been assembled, among them 71 assembled from type material [19]. The genomic studies
have revealed that Amycolatopsis species have genomes from 5.62 Mb (A. granulosa DSM
45669) to 10.94 Mb (A. anabasis EGI 650086) (on average, approximately 8.5–9 Mb), circular
chromosome, and a high DNA GC content (of 66–75 mol%.) The pan-genome analysis
revealed a core genome of 1212 genes with an accessory genome of 27,483 genes and 33,342
unique genes [20,21]. Due to such a significant pan-genome, Amycolatopsis species have
an extensive adaptive capacity. A major part of the accessory and unique genes of the
Amycolatopsis strains are involved in secondary metabolite biosynthesis [20,22].
The diversity of secondary metabolites in bacteria is highly dependent on the genus
and is mainly organized into several diverse clusters called biosynthetic gene clusters
(BGCs), which contain biosynthesis genes in close physical proximity [23–26]. BGCs
encoding for closely related biosynthetic pathways are summarized under the term gene
cluster families. All members of the cluster either produce or possess biosynthetic genes
for the production of the corresponding class of antibiotics. BGCs of various genera
of actinobacteria retrieved from the repository MIBiG (Minimum Information about a
Biosynthetic Gene cluster) are presented in Table 1. The correlation between average
total genome length and number of BGCs puts Amycolatopsis in second place among rare
actinobacteria species.
Antibiotics 2021, 10, 1254 3 of 25
Figure 1. (A). Amycolatopsis orientalis—vancomycin producer. (B). Taxonomy position of the genera Amycolatopsis. Nomen-
clatural status of species: validly published [18]. Note: *—species that are described as antibiotics producers.
Table 1. Number of identified biosynthetic gene clusters for various genera of actinobacteria.
Average Total Genome Length Number of Biosynthetic

Genus
(Mb) [19] Gene Clusters [25]
Actinoplanes 9 11
Actinomadura 9 10
Amycolatopsis 9 25
Micromonospora 7 26
Nocardia 8 6
Streptomyces 9 637
Streptosporangium 10 3
Phylogenetic trees constructed with the oxyB monooxygenase gene (essential for
glycopeptides production) or with the AHBA synthase gene (essential for ansamycins
production) demonstrate that all strains with correspondent genes are grouped into in-
dividual cluster families [27]. So, Amycolatopsis type strains that produce, or have the
potential to produce, a particular class of antibiotic are phylogenetically related. Owing
to this phylogenetic clustering, it is possible to predict the antibiotic-production ability of
a novel Amycolatopsis strain by its association in the tree, constructed with the antibiotic
biosynthetic gene sequences. It should be noted that the presence of these genes does not
necessarily mean that the strains will produce the antibiotic. The genes may not be ex-
pressed at all in the strain (silent genes) or may only be expressed under specific conditions
(e.g., under particular environmental conditions, such as the type of media used for the
antibacterial testing). Furthermore, if the genes are expressed, the antibiotic may not have
Antibiotics 2021, 10, 1254 4 of 25
activity against the strains used in the antibacterial screening tests. It is interesting to note
that antibiotic biosynthetic genes in several Amycolatopsis type strains that are not known
to produce antibiotics have been detected.
3. Amycolatopsis Genomic Potential for Antibiotic Production

Today, understanding of the BGC system functioning, together with next generation se-
quencing, allows us to predict detection of new antibiotics. In 2006, genomic scanning anal-
yses of A. orientalis ATCC 43491, deposited as a vancomycin producer, revealed the presence
of genetic loci to produce at least ten secondary metabolites other than vancomycin [28].
Screening of culture liquids led to the isolation of a novel linear polyene antibiotic 13-
hydroxy-2,12,14,16,22-pentam ethyl-28-(N-methyl-guanidino)octacosa-2,4,6,8,10,14,20,24-
octaenoic acid (2-hydroxy-5-oxo-cyclopent-1-enyl)-amide, ECO-0501), which exhibited
antibacterial activity against several resistant Gram-positive pathogens.
Bacterial genome sequences are checked for regions that are likely to encode the pro-
duction of secondary metabolites. Now researchers are faced with another problem: in BGC
it is easy to identify bioinformatics, but how do we get them to produce antibiotics in the
laboratory? Xu et al. reported a method for activating silent BGCs in diverse microorgan-
isms [29]. This approach relies on elicitor screening to induce the secondary metabolome
of a given strain and imaging mass spectrometry to visualize the resulting metabolomes
in response to ~500 conditions. Because it does not require challenging genetic, cloning,
or culturing procedures, this method can be used with both sequenced and unsequenced
bacteria. Application of this method to Amycolatopsis keratiniphila NRRL B24117 allowed
the discovery of nine glycopeptide chemotype metabolites with potentially therapeutic
bioactivities. Keratinimicins A and C showed potent antibacterial activity against numer-
ous Gram-positive pathogens, with minimal inhibitory concentrations (MICs) akin to those
of vancomycin against streptococci, Clostridium difficile, and Enterococcus faecalis.
On the one hand, the detection of ECO-0501 and keratinimicins is a worthy example
of using the genome scanning method to identify and isolate a new class of antibacte-
rial preparations. However, on the other hand, genomic mining has not become a key
technology for the extraction of natural secondary metabolites. Most natural product
BGC identified in bacterial genomic and metagenomic sequencing efforts are silent under
laboratory growth conditions. Kim et al. presented a BGC activation method where the
gene clusters are disassembled at interoperonic regions in vitro using CRISPR/Cas9 and
then reassembled with PCR-amplified, short DNAs carrying synthetic promoters, using
transformation-assisted recombination in yeast [30]. This is in vitro disassembly/in vivo
reassembly method was used for the activation of the atolypene BGC from the genome
of the cultured actinomycete Amycolatopsis tolypomycina NRRL B-24205.30, which led to
the characterization of two bacterial cyclic sesterterpenes, atolypene A and B, which are
moderately cytotoxic to human cancer cell lines.
The most significant antibiotics from the Amycolatopsis genus were isolated by the
traditional method, which involves isolation and cultivation of actinobacteria from the
soil, screening for inhibitory activity in a test tube, and isolation of the leading molecules.
The most currently known antibiotics isolated from Amycolatopsis are summarized in
Table 2. There are more than 100 compounds of Amycolatopsis origin with described
antibacterial activity and/or proven antibiotic biosynthesis gene presence. The most
productive species are A. orientalis (12 antibiotics), A. mediterranei (5 antibiotics), and A.
sulphurea (3 antibiotics). Among the antibiotics produced by Amycolatopsis, there are two
main commercially significant groups: glycopeptides and polyketides. Further in the text
of this review we will discuss this division.
Antibiotics 2021, 10, 1254 5 of 25
Table 2. Representatives of the genus Amycolatopsis and the antibiotics they produce.
Species, Strains Antibiotics Properties References

Antimicrobial activity against Gram-positive bacteria
Amycolatopsis sp. 17128 Mutactimycin A, D, E [31]
(including MRSA 1 )
Amycolatopsis sp. Cra33g Amycolactam Significant cytotoxicity [32]
Amycolatopsis sp. Hca4 Rifamorpholines A–E [13]
(including MRSA)
Antimicrobial activity against Gram-positive and
Amycolatopsis sp.
Pradimicin-IRD Gram-negative bacteria; [33]
IRD-009
Cytotoxic activity against cancer cell lines
Dipyrimicin A exhibits strong antimicrobial and cytotoxic
Amycolatopsis sp. activities;
Dipyrimicins A and B [34]
К16-0194 Dipyrimicin B exhibits antimicrobial activity against
Escherichia coli
Siderochelin A exhibits antimicrobial activity against
Gram-positive bacteria and Escherichia coli;
Amycolatopsis sp. LZ149 Siderochelins A, D, E, and F [35,36]
Siderochelins A, D and E exhibit antimicrobial activity against
Mycobacterium smegmatis
Macrotermycins A and C had antimicrobial activity against
Gram-positive bacteria (particularly staphylococcal
Amycolatopsis sp. M39 Macrotermycins A–D infections); [14]
Selective antifungal activity (against a fungal parasite of the
termite fungal garden)
Amycolatopsis sp. Antimicrobial activity against Gram-positive bacteria
Amythiamicins A, B, C and D [37,38]
MI481-42F4 (including MDR 2 strains)
Antimicrobial activity against Gram-positive pathogenic
Amycolatopsis sp. infections (particularly staphylococcal infections);
Ristocetin (Ristomycin) [39–41]
MJM2582 Applied to the in vitro diagnosis of conditions such as von
Willebrand disease and Bernard–Soulier syndrome
Antimicrobial activity against Staphylococcus aureus strains
Amycolatopsis sp. Рargamicins A (including MRSA) and Enterococcus faecalis, E. faecium strains [42]
ML1-hF4 (including VRE 3 )
Weak activity against Gram-positive and Gram-negative
bacteria;
Valgamicins A, C, T and V [43]
Valgamicins A, C and T exhibit moderate cytotoxicity against
human tumor cell lines
Amycolatopsis sp.
Amycophthalazinone A Weak antimicrobial and antifungal activities [44]
YIM 130642
Amycolatopsis sp. 2-carbamoyl-3-hydroxy-1,4- Strong antimicrobial (including MRSA) and antifungal
[45]
YIM 130687 naphthoquinone activities
Amycolatopsis sp. AA4 Amycomicin Strong antimicrobial activity against Staphylococcus aureus [46]
1(10-aminodecyl) pyridinium Gram-negative bacteria; [47]
Cytotoxic activity against cancer cell lines
A. alba Kigamicins A-E (including MRSA); [48,49]
Kigamicin D is an anticancer agent
Maytansinoids 7 and 13 showed antitumor activities against
Maytansinoids 1–14 [50]
four human cancer cell lines
A. australiensis Antibiotic biosynthetic genes were identified [27]
Azureomycins A and B Strong antimicrobial activity against Gram-positive bacteria [51,52]
A. azurea Very weak or no activity against Gram-positive and
Оctacosamicins A and B Gram-negative bacteria; [53,54]
Moderate activity against fungi and yeast
A. balhimycina Balhimycin [55]
(including MRSA)
Antimicrobial activity against Gram-positive bacteria;
A. coloradensis Avoparcin (avotan) [56–58]
Animal growth promoter
A. decaplanina Decaplanin [59,60]
(including antibiotic-resistant enterococci and clinical isolates)
A. hippodromi Amycolasporins A−C [61]
Gram-negative bacteria
Antimicrobial activity against Gram-positive bacteria,
(particularly staphylococcal infections);
A. japonica Ristocetin (Ristomycin) [62]
Applied to the in vitro diagnosis of conditions such as von
Antibiotics 2021, 10, 1254 6 of 25
Table 2. Cont.

A. jejuensis Antibiotic biosynthetic genes were identified [63]
Keratinimicins A and C exibit strong antimicrobial activity
against Gram-positive bacteria (particularly staphylococcal
Keratinimicins A–D;
A. keratiniphila infections); [29]
Keratinicyclin A–C
keratinicyclin B exibit moderate antimicrobial activity against
Streptococcus spp. and Clostridium difficile
A. keratiniphila subsp. keratiniphila Antibiotic biosynthetic genes were identified [27]
A. keratiniphila subsp. nogabecina Nogabecin (Actinoidin B) Antimicrobial activity against Gram-positive bacteria [64,65]
Cephamycin C Gram-negative bacteria (including resistant strains); very [66–69]
A. lactamdurans * efficient antibiotic against anaerobic microbes
Efrotomycin Antimicrobial activity against Gram-positive bacteria [68,70]
A. lurida Benzanthrins A and B [71,72]
Inhibit the growth tumor cells in tissue culture
Antimicrobial activity against Gram-positive bacteria,
(particularly staphylococcal infections);
A. lurida Ristocetin (Ristomycin) [41,73,74]
Applied to the in vitro diagnosis of conditions, such as von
Amexanthomycins A–J Inhibitory activity against human DNA topoisomerases [75]
Dethymicin (including MRSA); [76]
A. mediterranei Immunosuppressant
Kanglemycin A (including rifampicin-resistant ones and M. tuberculosis with [77,78]
MDR)
Strong antimicrobial activity against Gram-positive bacteria
Rifamycines [79–83]
(particularly mycobacteria)
Tetracenomycin Х [84,85]
Showed antitumour activity in vivo
A. minnesotensis Antibiotic biosynthetic genes were identified [27]
A. nigrescens Antibiotic biosynthetic genes were identified [27]
A. niigatensis Antibiotic biosynthetic genes were identified [27]
A last-line drug for the treatment of infections caused by
Vancomycin almost all clinically significant Gram-positive bacteria [3,86]
(including MRSA)
N–Demethylvancomycin [87–90]
(including MRSA)
N,N–Demethylvancomycin Antimicrobial activity against Gram-positive bacteria [91]
Norvancomycin [92,93]
(particularly MRSA and MRSE 4 )
A. orientalis
Quartromicin (the complex of at least
Antiviral activity against herpes simplex virus type 1,
six antibiotics components A1, A2, A3, [94]
influenza virus type A and human immunodeficiency virus
D1, D2, and D3)
Strong antimicrobial activity in vitro and in vivo against the
UK-69753 swine Gram-negative anaerobic pathogen Treponema [95,96]
hyodysenteriae
MM 47761 and MM 4972; MM 55266,
Antimicrobial activity against Gram-positive bacteria [97,98]
and MM 55268
Eremomycin B Antimicrobial activity against Gram-positive bacteria [99–101]
Orienticins A-D Antimicrobial activity against S. aureus (including MRSA) [102]
Chloroorienticins A-E Antimicrobial activity against S. aureus (including MRSA) [103]
LY264826 [104]
(including MRSA)
Strong antimicrobial activity against Gram-positive bacteria
ECO-0501 [28]
(including MRSA and VRE)
A. palatopharyngis Antibiotic biosynthetic genes were identified [27]
A. regifaucium Kigamicins A-E (including MRSA); [48,105–107]
Kigamicin D is an anticancer agent
Moderate antimicrobial activity against Gram-positive
A. rifamycinica Tetracenomycin Х organisms (including resistant strains); [108,109]
Activity against certain tumor cell lines
Antibiotics 2021, 10, 1254 7 of 25
Table 2. Cont.

Antibiotic biosynthetic genes were identified;
A. roodepoortensis [24]
Antimicrobial activity against Gram-positive (particularly mycobacteria) and Gram-negative bacteria
A. rubida Antibiotic biosynthetic genes were identified [27]
Strong antimicrobial activity against drug-resistant
A. saalfeldensis Saalfelduracin [110]
Gram-positive bacteria
Antibiotic biosynthetic genes were identified;
A. speibonae [24]
Antimicrobial activity against Gram-positive bacteria (particularly mycobacteria)
Echinosporin Antifungal activity against root-rot pathogens of the Panax
A. speibonae [111]
7-deoxyechinosporin notoginseng
Epoxyquinomicins A and B exhibit antimicrobial activity
against Gram-positive bacteria;
Epoxyquinomicins C and D exhibit almost no antimicrobial
Epoxyquinomicins A-D [112,113]
activity and no cytotoxicity;
All these antibiotics showed improvement of collagen
A. sulphurea induced arthritis in vivo
Moderate antimicrobial activity against Gram-positive
Azicemicins A and B [114,115]
bacteria (particularly mycobacteria)
Chelocardin (Cetocycline) Gram-negative (including tetracycline-resistant pathogens [116–118]
and MDR pathogens)
A. taiwanensis Antibiotic biosynthetic genes were identified [27]
Antibiotic biosynthetic genes were identified [27]
A. thermoflava Antibiotic biosynthetic genes were identified
1-methoxy-3-methyl-8-hydroxy-
Anticancer activity against lung cancer and lymphoblastic [119]
anthraquinone
leukemia cells
A. tolypomycina Tolypomycin Strong antimicrobial activities against Gram-positive bacteria [65,120]
A. tucumanensis Antibiotic biosynthetic genes were identified [27]
A. umgeniensis Eremomycin B Antimicrobial activity against Gram-positive bacteria [121]
A. vancoresmycina Vancoresmycin [122,123]
(including resistant strains)
A. xylanica Antibiotic biosynthetic genes were identified [27]
1
Strong antimicrobial activity—MIC ≤ 1 µg/mL, moderate—MIC 1–16 µg/mL, weak—MIC ≥ 16 µg/mL. MRSA—methicillin-resistant
S. aureus; 2 MDR—multiple drug resistance; 3 VRE—vancomycin-resistant enterococci; 4 MRSE—methicillin-resistant S. epidermidis; *
Nomenclatural status: not validly published.
4. Glycopeptide Antibiotics
Glycopeptides are glycosylated non-ribosomal peptides produced by a various group
of actinomycetes. Glycopeptide antibiotics have a common structure representing a hep-
tapeptide containing aromatic amino acids that have undergone extensive oxidative cross-
linking to form macrocycles and carry in various positions such motifs as sugar residues,
chlorine atoms, and lipid chains [124]. Among actinobacteria, A. orientalis is a well-known
producer of glycopeptide antibiotics (Table 2).
Chen et al. proposed the dividing of glycopeptide antibiotics produced by Amycolatop-
sis into three classes, based on residue type at positions 1 and 3 of the heptapeptide: (I)
Compounds containing aliphatic residues (vancomycin, balhimycin, eremomycin, chloroer-
emomycin, orienticin, norvancomycin). Vancomycin and balhimycin contain two sugar
residues, while eremomycin and orienticin contain three sugar residues. (II) Compounds
containing aromatic residues (avoparcin). (III) Compounds with aromatic residues that
are covalently joined to each other (ristocetin) [3]. The structures of the main glycopeptide
antibiotics are presented in Figure 2.
Antibiotics 2021, 10, 1254 8 of 25
Figure 2. Glycopeptide antibiotics: (1) vancomycin, (2) norvancomycin, (3) eremomycin, (4) bal-
himycin, (5) ristocetin, (6) avoparcin, and (7) keratinimicin A.
4.1. Vancomycin
In 1952, a missionary in Borneo sent a soil sample to his friend Dr. E.K. Cornfield, an or-
ganic chemist at Eli Lilly and Company [125]. The microorganism isolated from this sample
(previously identified as Streptomyces orientalis) produced a substance (“compound 05865”)
that was active against most Gram-positive organisms, including penicillin-resistant S.
aureus. Тhe original product, obtained by fermentation, contained considerable (up to
70%) amounts of impurities, and had a brown color, earning it the nickname “Mississippi
Mud” [126]. The resulting drug was named “vancomycin”, a term derived from the word
“vanquish” [127]. The A. orientalis type strain was used for the biological preparation of
vancomycin. However, A. orientalis is also a producer of natural derivatives of vancomycin,
N-demethylvancomycin and N,N-demethylvancomycin, which demonstrate significant
antibacterial activity [87,91]. Subsequently, numerous mutant strains of A. orientalis were de-
veloped for the industrial production of vancomycin, giving a high yield of the drug [128].
In 1958, there was a growing problem of drug-resistant staphylococci, so the US Food and
Drug Administration granted vancomycin a “fast track approval” in the absence of an
effective alternative [126,129]. However, methicillin, the first semisynthetic penicillin, was
Antibiotics 2021, 10, 1254 9 of 25
also licensed for clinical use in 1958. The pronounced ototoxicity and nephrotoxicity, most
likely due to impurities contained in early vancomycin lots, did not allow its widespread
use for treatment. A special place among adverse reactions is occupied by the “red man”
syndrome, which is characterized by a combination of erythema, pruritis, hypotension, and
angioedema. The occurrence of “red man” syndrome is associated with the degranulation
of mast cells and basophils caused by the administration of rapid infusions of the first
dose of the drug [130]. The aversion to vancomycin is associated with the emergence of
methicillin-resistant, and broadly, beta-lactam resistant S. aureus, and the introduction of
chromatographic purification methods. Chromatographically purified dosage forms of
vancomycin with a content of at least 90–95% of the active substance are characterized
by low toxicity, and today vancomycin is considered as a relatively safe drug with some
minor side effects. Vancomycin and related glycopeptides are considered antibiotics of
last resort for the treatment of life-threatening infections caused by all clinically significant
Gram-positive human pathogens, such as Clostridium spp., Enterococcus spp., Lactobacillus
spp., Streptococcus pneumoniae, S. aureus (including methicillin-resistant strains of S. aureus,
MRSA), etc [124,131]. During the vancomycin biosynthesis, seven amino acid precursors
are assembled to form a linear heptapeptide, which is then modified, including cyclization,
halogenation, methylation, and glycosylation [132–134] (Figure S1). Both methylation and
demethylation do not affect the antibacterial activity of vancomycin and its derivatives
in vitro. As for glycosylation, despite aglucovancomycin showing a slightly higher bioac-
tivity than that of vancomycin in vitro, the in vivo activity was five-fold lower than that
of vancomycin [135]. This indicates that part of the sugar may play an important role in
giving improved pharmacokinetic properties [135]. Chlorination has not been sufficiently
studied, although it is assumed that it improves the dimerization of glycopeptides, which,
in turn, can positively enhance antimicrobial activity [133]. The biosynthesis pathways of
balhimycin and chloroeremomycin are similar to vancomycin [3].
4.2. Eremomycin
Eremomycin was isolated at the Gause Institute of New Antibiotics (Russia) from
the cultural liquid of the actinomycete Nocardia orientalis INA 238, later clarified as A.
orientalis [136]. Eremomycin is closely related to vancomycin but differs in sugar residue
and chlorine content. Monodechlorovancomycinic acid was detected in eremomycin.
The antibacterial spectrum of eremomycin is close to that of ristomycin and vancomycin.
However, the in vitro antibacterial activity of eremomycin is 2–10 times higher than that
of ristomycin and vancomycin. In vivo studies showed that eremomycin is less toxic than
vancomycin and ristomycin. It does not cause damage to local tissues after intramuscular
injections. The chemotherapeutic indices of eremomycin in the treatment of staphylococcal
and streptococcal sepsis in albino mice exceeded 10 times those of vancomycin [137]. The
pharmacokinetic parameters of eremomycin, teicoplanin, and vancomycin were compared
after their intravenous administration to rats at the same dose. The antibacterial activity of
eremomycin against methicillin-resistant S. aureus (MRSA) was 4 times higher than that of
vancomycin [138]. Currently, the ability to produce eremomycin is shown not only for A.
orientalis but also for A. umgeniensis [121].
4.3. Norvancomycin
Norvancomycin was isolated from A. orientalis CPCC200066 (originally named wan-
23) from a soil sample in China in 1959 [93]. This strain was first discovered for its ability
to produce an antibiotic that resembles the glycopeptide antibiotic vancomycin, and in
1983 it was confirmed as norvancomycin. The chemical structure of norvancomycin is
almost the same as that of vancomycin, except for an absent methyl group at the N-
terminus. Norvancomycin is effective for the treatment of bacterial infections caused by
Gram-positive cocci and bacilli, especially infections of MRSA and methicillin-resistant S.
epidermidis (MRSE) [92]. The complete genome sequence of A. orientalis CPCC200066 has
Antibiotics 2021, 10, 1254 10 of 25
been obtained [93]. Norvancomycin is widely used in China to treat severe infections such
as endocarditis and osteomyelitis.
4.4. Balhimycin
Balhimycin was isolated from the fermentation broth of a Amycolatopsis sp. Y-86,
21022, later clarified as A. balhimycina. It differs from vancomycin only in its glycosylation
pattern [55]. Balhimycin is very similar in activity to vancomycin, but it shows higher ac-
tivity towards anaerobic bacteria. Most knowledge on glycopeptide biosynthetic pathways
comes from studies on A. balhimycina as this species, among glycopeptide producers, is
genetically more amenable [139]. A. balhimycina is positioned as a model producing strain
for production of improved derivatives of glycopeptide antibiotics by molecular genetic
methods [140].
4.5. Ristocetin (Ristomycin)

Ristocetin was isolated from A. orientalis subsp. lurida [41,73]. It was first discovered
as a mixture of two closely related components, designated ristocetin A and ristocetin B.
Although these two ristocetins have the same antimicrobial spectrum, ristocetin B is 3–4
times more active than ristocetin A. The commercial preparation of this antibiotic is the
mixture of ristocetin A and ristocetin B [141]. Ristocetin A and B are specific against Gram-
positive bacteria, including mycobacteria. Since the toxic side effects of ristocetin include
thrombocytopenia and platelet agglutination, it is only used for laboratory diagnosis of
von Willebrand disease. Von Willebrand disease is a mucosal bleeding caused by platelet
and collagen binding [142]. One of the strategies to new antibiotics discovery is to evaluate
the genetic capacity of the secondary metabolite-producing strains and to activate silent
BGC. A. japonicum does not produce antibiotics under standard laboratory conditions. To
activate a possible silent glycopeptide cluster, Spohn et al. introduced a gene encoding
the transcriptional activator of balhimycin biosynthesis, the bbr gene from A. balhimycina
(bbrAba ), into A. japonicum. The resulting recombinant strain of A. japonicum/pRM4-bbrAba
synthesizes ristomycin A [62].
4.6. Avoparcin and Emergence of Vancomycin Resistance

Avoparcin (avotan) was isolated from A. coloradensis (formerly Streptomyces candidus)
in 1968 [56]. It is chemically similar to vancomycin and is a mixture of components. The
commercial product consists of a mixture of α- and β-avoparcin, which differ only in the
presence of an additional aromatic chlorine atom in the β component [143,144]. Avoparcin
has been widely used as a feed additive to promote the growth of cattle, pigs, and chickens.
The presence of vancomycin-resistant bacterial strains in humans who were first admitted
to the hospital and had never previously taken antibiotics suggested that these strains could
have been transmitted through the food chain, as a result of the use of avaporcin in animal
feed. The presence of various strains of vancomycin-resistant enterococci strains in animal
and human feces in areas where avoparcin was used has been well documented [145]. So,
avoparcin was banned in Europe in 1997 by the Commission of the European Union, after
which many researchers reported decreased prevalence of vancomycin-resistant enterococci
strains in livestock. However, these strains never completely disappeared [146,147].
Antimicrobial activity of glycopeptides is based on binding to the bacterial cell enve-
lope, and not to the target protein, as in the case of most antibiotics. Glycopeptides bind to
the D-alanyl-D-alanine (D-Ala-D-Ala) dipeptide terminus of the growing peptidoglycan
on the outer surface of the bacterial cytoplasmic membrane [148]. This, in turn, interferes
with the maturation of the peptidoglycan layer, sequestering the substrate from transpepti-
dation and/or transglycosylation reactions at the late extracellular stages of peptidoglycan
cross-linking. Subsequently, the replicating bacteria cannot survive due to an incomplete
and damaged cell wall, which makes them vulnerable to osmotic pressure [124]. Due to
a different cell wall morphology, namely the presence of an external lipopolysaccharide
membrane impervious to large biomolecules, Gram-negative bacteria are protected from
Antibiotics 2021, 10, 1254 11 of 25
vancomycin [149]. Glycopeptide-resistant organisms replace the D-Ala-D-Ala terminus

with D-alanyl-D-lactate (D-Ala-D-Lac) or D-alanyl-D-serine (D-Ala-D-Ser), thus markedly
reducing antibiotic affinity for the cellular target [150]. Resistance manifests itself in entero-
cocci and staphylococci mainly through the expression of van genes encoding proteins that
reprogram cell wall biosynthesis and thus evade the action of the antibiotic [124].
The emergence of vancomycin resistance was compared to all other antibiotics. In 1986,
vancomycin-resistant Enterococcus faecium was found in England and France, followed by
vancomycin-resistant E. faecalis detected in the United States next year [151]. Vancomycin-
resistant enterococci (VRE) are categorized as opportunistic pathogens that are selected
for when other bacteria die off. The determinants of resistance in enterococci are encoded
in the plasmid-borne transposons, which increases the vancomycin resistance spreading
among Gram-positive species through horizontal gene transfer [152,153]. The transfer of
van genes from enterococci to other Gram-positive bacteria, such as staphylococci, has been
shown [154]. The first case of S. aureus resistance to vancomycin was detected in 2002 for a
dialysis patient in Michigan co-infected with the vancomycin-resistant E. faecalis [129,155].
The origin of the genes associated with vancomycin-resistance in enterococci is unknown,
but the selection pressure on bacteria was clearly favorable for their occurrence. At the
same time, the use of avoparcin in livestock farming has created a hospitable environment
for the emergence of vancomycin-resistant enterococci strains. However, it is possible that
actinomycetes are the original source of the van genes. Most antibiotic-producing bacteria
have self-defense strategies and immunity from the effects of these chemical weapons. The
simultaneous presence of the antibiotic synthesis and antibiotic resistance genes makes
it possible to regulate the bacterial self-resistance [156]. It has been hypothesized that
the enterococci vancomycin-resistance genes originated from glycopeptide-producing
organisms where they are presumably needed to avoid bacterial suicide [157,158]. Then,
the resistance genes were transferred to organisms with the same GC content (for example,
Paenibacillus popilliae), and then to enterococci. In support of this hypothesis, van-like genes
which have similarity to vanA and vanB have been found in several glycopeptide producers
such as A. orientalis and A. balhimycina.
5. Polyketide Antibiotics
In addition to glycopeptide antibiotics, the genus Amycolatopsis is a well-known
producer of polyketide antibiotics. Their structures range widely and include cyclic, acyclic,
small, large, simple, and complex molecules (Figure 3). Among the polyketide antibiotics
produced by genus Amycolatopsis, rifamycins, chelocardin, tolypomycin, kanglemicin A,
macrothermycins A-D, vanсoresmycin, tetracenomycin X, and rifamorpholines A-E should
be listed (Table 2). These antibiotics are united by their bacterial biosynthetic pathway: all
of them are obtained through a polyketide precursor, which is different in the case of each
antibiotic. The most commercially demanded of them is rifamycin, which belongs to the
ansamycin polyketides. Ansamycins get their name from the characteristic configuration
of their molecule carbon skeleton, which has a basket-shaped architecture, consisting of an
aromatic naphthalene (or benzene) core and a long aliphatic bridge in the shape of a handle
(latin, ansa) connecting two non-adjacent positions of the core. The resulting molecules are
very rigid and compact, which leads to unique chemical properties and specific biological
effects [159].
Antibiotics 2021, 10, 1254 12 of 25
Figure 3. Polyketide antibiotics: (1) rifamycin B, (2) kanglemycin A, (3) vancoresmycin, (4) chelocardin, (5) rifamorpholine B.
5.1. Rifamycin’s Discovery and Structure

In 1957, in France, from a soil sample in Saint-Raphael, a strain was isolated which
was classified as Streptomyces mediterranei, later as Nocardia mediterranei, and finally as
Amycolatopsis mediterranei ATCC 13685/DSM 43304/ME 83/973. The strain was cultured
in shaking flasks and the cultural liquid showed high activity against Gram-positive
bacteria Mycobacterium tuberculosis. In addition, it demonstrated limited activity against
some Gram-negative bacteria [79]. Thus, one of the earliest antibiotics was discovered,
rifamycin, named after the Italian movie “Le Riffi” [160]. The original strain A. mediterranei
ATCC 13685 produced a mixture of several rifamycin antibiotics. The only component
of this extract that could be isolated in pure crystalline form by the addition of sodium
diethylbarbiturate was rifamycin B, secondary in biological activity. The rifamycin B
molecule consists of two main parts: the naphthoquinone ring and a 24-member aliphatic
chain with 5 methyl groups (Figure 3(1)). Due to the importance of rifamycin, the producer
strain A. mediterranei was selected in order to create strains capable of producing large
amounts of rifamycin B, or its biologically active natural derivatives [161]. Later, a mutant
strain, A. mediterranei ATCC 21789, producing single rifamycin B without any barbiturate
salt addition, was isolated [162].
All ansamycins are assembled by the polyketide pathway, using 3-amino-5-hydroxybenzoic
acid (AHBA) as the starting unit [163]. The earliest macrocyclic precursor in the biosynthesis of
rifamycin is proansamycin X (Figure S2). It had never been isolated and identified, therefore, it
is to some extent hypothetical [163,164]. Proansamycin X dehydrogenation leads to the forma-
tion of biologically inactive rifamycin W. Further post-translational modifications lead to the
production rifamycin SV, and rifamycin S [165]. Rifamycins W, S, and SV are key intermediates
in biosynthesis and are precursors of many other natural derivatives of rifamycins: B, R, G, Q, P,
Antibiotics 2021, 10, 1254 13 of 25
Z, O, L, Y, etc. Table 3 summarizes the rifamycin derivatives produced by genus Amycolatopsis

and shows their bioactivity and biosynthetic precursors. Some of these derivatives, together
with ketides accumulated by A. mediterranei, can be considered as waste metabolites, resulting
from enzymatic reactions with the formation of biologically active rifamycins. The most stable
component in the rifamycin complex is rifamycin B. Reversible oxidation of the quinone core,
followed by hydrolytic loss of the glycolic acid fragment of rifamycin B, leads to the production
of significantly more active rifamycins S and SV. Rifamycin SV quickly stood out among the
first available natural rifamycins due to its antibacterial activity and low toxicity. Rifamycin
SV was the first rifamycin used in clinical practice but was only effective when injected intra-
venously [166]. Rifamycin S was half as weak as rifamycin SV [167]. The poor bioavailability
and poor pharmacokinetic properties of rifamycin SV, combined with the understanding of
structure–activity relationships, initiated a chemical campaign to develop a more potent and
orally bioavailable drug. In 1965, Dow-Lepetit Research Laboratories (Milan, Italy) developed
rifampicin (3-(4-methyl-piperazinyl-iminomethyl) rifamycin SV), which is the most important
and widely used semi-synthetic antibiotic of the rifamycin group in medicine (Figure S2) [168].
Table 3. Rifamycins and related metabolites produced by actinobacteria of the genus Amycolatopsis.
Rifamycin Metabolites Possible Precursor Properties References

The first hypothetical macrocyclic intermediate of rifamycin biosynthesis has never been
Proansamycin X [83,169]
isolated and identified
No activity against Gram-positive bacteria or
Protorifamycin I (8-deoxyansamycins W) Proansamycin X [170]
modified protorifamycins (derived from
protorifamycin I) and defective rifamycins Protorifamycin I No antibiotic activity [171,172]
(8-deoxyrifamycins)
Rifamycin W Proansamycin X [173]
Rifamycin Z Rifamycin W [174]
No significant antibacterial, antifungal, or
31-Homorifamycin W Rifamycin W [81]
antiviral activity
Strong activity
Rifamycin SV Rifamycin W against Gram-positive bacteria (particularly [175,176]
mycobacteria)
Strong activity
Rifamycin S Rifamycin SV against Gram-positive bacteria (particularly [175]
mycobacteria)
Strong activity
Rifamycin R Rifamycin S against Gram-positive bacteria (particularly [177]
mycobacteria)
Rifamycin G Rifamycin S Activity against M. tuberculosis [178]
Rifamycin Y Rifamycin B Antibiotically inactive [179,180]
Rifamycin YO, YS, Isorifamycin Y Rifamycin Y Antibiotically inactive [179]
Protorifamycin B, 34a-deoxy-rifamycin W,
Rifamycin W-28-desmethyl-28-carboxy, Rifamycin Rifamycin W No data [181]
W-hemiacetal
Rifamycin O Rifamycin L Activity against M.abscessus [164,182,183]
Thiazorifamycins:
Rifamycin S No data [184]
Rifamycin Q, Rifamycin P, Rifamycin Verde
Good antimicrobial activity against Gram-positive
Rifamycin L Rifamycin S [164,185]
and Gram-negative bacteria
Activity against Gram-positive bacteria
Rifamycin B Rifamycin S [79,164]
(particularly mycobacteria)
27-Demethoxy-27-hydroxyrifamycin derivatives Rifamycin SV Activity against several Gram-negative bacteria [186]
Ansamycins W type are devoid of any biological
3-Hydroxyrifamycin S and further novel
Rifamycin S and W, respectively activity. Other ansamacins exhibit activity against [187]
ansamycins S, G and W type
Gram-positive and Gram-negative bacteria
Rifamorpholines B and D exhibit antimicrobial
Rifamorpholines A-Е Rifamycin S activity against methicillin-resistant S. aureus [13]
(MRSA)
Strong antimicrobial activity—MIC ≤ 1 µg/mL, moderate—MIC 1–16 µg/mL, weak—MIC ≥16 µg/mL.
Antibiotics 2021, 10, 1254 14 of 25
5.2. Mechanism of Rifampicin Action and Occurrence of Resistance

The antibiotic activity of rifamycins on the bacterial cell has been most widely studied
for rifampicin. Rifampicin (and other rifamycins) binds in the rifamycin-binding pocket
to the β-subunit of RNA polymerase in the immediate vicinity of the catalytic site and
sterically blocks the expansion of the RNA chain [167]. The collision of RNA and rifampicin
occurs when the RNA reaches a length of 3–4 nucleotides, after which the RNA is released
from the promoter complex in the form of an interrupted transcript. The length of the
abortive RNA product may be affected at the C3 substituent of a particular rifamycin’s
derivative. Eukaryotic cell polymerases are less sensitive to the antibiotic compared to
the bacterial ones. Binding constants for prokaryotic RNA polymerases are about 10−8 M
whereas those for eukaryotic enzymes are at least 10,000 fold weaker [167]. Due to their high
selectivity for their molecular target, rifamycins have become a safe and effective drug [78].
At present, rifampicin is still the first-line treatment for diseases such as tuberculosis,
leprosy, and various infections associated with the biofilm formation. It is important to
note that natural rifamycins have significant activity only against Gram-positive bacteria
because of the hydrophobic nature of their large molecule.
The main practical rifamycin application is associated with its activity against my-
cobacteria. Tuberculosis is second (just after AIDS) among the world’s most common
causes of death from infectious diseases [188]. WHO estimates that 8–10 million new cases
of tuberculosis occur worldwide each year. A third of the world’s population is infected
by M. tuberculosis, the etiological agent of tuberculosis [189,190]. However, long periods
of use and poor medical supervision have resulted in rifamycin-resistant M. tuberculosis
strains [191]. The primary mechanism of resistance to rifampicin (and other rifamycins)
consists of rapid selection of resistant mutants (amino acids substitutions) in the rifampicin-
binding pocket of RNA polymerase, which results in antibiotic affinity decreasing. Another
way to decrease antibiotic affinity is the enzymatic modification of rifamycin by C-21 and
C-23 hydroxyl groups [192]. Altogether, these modifications generate the rifamicyn resis-
tome, which negatively affects this class of antibiotics. In 2016, there were 600,000 reported
new cases of resistance to rifamycin, of which 490,000 were caused by multidrug-resistant
M. tuberculosis strains [78,193].
5.3. Polyketide Backbone Rearrangement

Despite obtaining a large number of rifamycin derivatives by semi-synthetic ap-
proaches (more than 750 rifamycin derivatives have been studied) the possibility of chemi-
cally introducing structural modifications is limited because of the structural complexity
of the rifamycin molecule [160,169]. Unfortunately, no new drug has been developed for
tuberculosis in recent decades [167]. Today, to achieve structural diversity, researchers have
switched to a combinatorial biosynthetic approach—mutasynthesis. Knowledge of the
biosynthesis of rifamycins allows the rational genetic manipulation of A. mediterranei to
obtain new natural antibiotics.
Nigam et al., by replacing the substituted acyltransferase domain of module 6 of
rifamycin polyketide synthase with that of module 2 of rapamycin polyketide synthase, ob-
tained the semisynthetic derivatives 24-desmethylrifamycin B and 24-desmethylrifamycin
SV. These compounds have proven effective against a number of pathogenic bacteria,
including several rifampicin-resistant M. tuberculosis strains [194].
Posttranslational modifications at the last stages of the biosynthetic pathway of ri-
famycins play an important role in expanding the structural diversity and, as a consequence,
biological activity of the final rifamycin metabolites. Table 3 shows that the early inter-
mediates on the pathway of rifampicin biosynthesis do not have any biological activity.
The proposed earliest macrocyclic precursor in rifamycin biosynthesis, proansamycin X,
undergoes dehydration to form protorifamycins or undergoes dehydrogenation to form
rifamycin W. Rifamycin W undergoes a rearrangement of the polyketide backbone to pro-
duce rifamycin B. However, the progress of genetic engineering allows us to look at inactive
rhymaicins X and W as potential sources for structural modifications in the hope of new
Antibiotics 2021, 10, 1254 15 of 25
drugs discovery. Shi et al. in 2021 constructed the mutant strain Amycolatopsis mediterranei
S699 ∆rif-orf5 by in-frame deleting the rif-orf5 gene (involved in the polyketide backbone
rearrangement mechanism) to afford thirteen rifamycin W congeners including seven new
ones [195]. Compounds 1–3 exhibited antibacterial activity against Staphylococcus aureus.
A year earlier, Ye et al. constructed mutant strain A. mediterranei S699∆rifT by deleting
the rifT gene, encoding NADH-dependent dehydrogenase, presumably responsible for
the dehydrogenation of proansamycin X. The mutant strain successfully produced eleven
8-deoxy-rifamycin derivatives and seven known analogs. For four of them, antibacterial
activity against S. aureus was shown [196].
6. Old New Polyenes

A promising approach to searching for effective antibiotics is to look back and re-
examine the molecules that previously demonstrated antibacterial activity but for various
reasons did not receive further development.
6.1. Kanglemycin A
As well as rifamycins, A. mediterranei produces another ansamycin—kanglemycin A (KglA).
KglA was originally isolated from the fermentation broth of Nocardia mediterranei var. kanglensis
1741–64 [77]. There was only limited information about its biological activity until 2018, when
Mosaei et al. described in detail the mechanism of KglA action [78]. This antibiotic contains two
important and unusual ansa bridge modifications: a pendant 2,2-dimethyl succinic acid side
chain at C20 and a unique sugar moiety (β-O-3,4-O,O’-methylene digitoxose) at C27. As a result,
KglA exhibits an altered binding conformation with RNA polymerase (larger binding surface)
in comparison to known rifamycins and their semisynthetic derivatives. The mechanism of
KglA action also differs from rifampicin, as KglA inhibits RNA synthesis even after the first
phosphodiester bond formation. This leads to the phenomenon where KglA is effective against
rifampicin-resistant pathogens [78,197].
6.2. Chelocardin (Otherwise Known as Cetocycline or Cetotetrine)

Another polyenes antibiotic produced by Amycolatopsis that has regained interest in
recent years is atypical tetracycline chelocardin. Isolated from A. sulphurea (formerly N.
sulphurea), chelocardin was first described in the 1970s [116,198]. It is structurally related
to tetracyclines and contains a 9-methyl group, aromatic ring, unsubstituted 4-ammonia
group, and the methyl group replacing the 2-ammonia group. At low concentrations,
like classical tetracyclines, chelocardin prevents bacterial growth by inhibition of peptidyl
transferase biosynthesis. At higher concentrations, the bacterial membrane is the main
antibiotic target of chelocardin [199]. The application of the biosynthetic engineering ap-
proach made it possible to design a recombinant A. sulphurea producing a new chelocardin
analogue with carboxamido moiety of tetracyclines (an important structural feature for
its bioactivity). 2-Carboxamido-2-deacetyl-chelocardin showed significantly improved
antimicrobial activity against a collection of well-characterized multidrug-resistant clinical
isolates from the ESKAPE panel [118,200,201].
6.3. Vancoresmycin
Vancoresmycin is an understudied natural product antibiotic consisting of a termi-
nal tetramic acid moiety linked to a linear, highly oxygenated, stereochemically complex
polyketide chain. It was isolated from the fermentation broth of the Amycolatopsis sp. ST
101170 in 2002 [122]. The species name A. vancoresmycina was proposed by Wink et al.
who isolated it from Indian soil [65]. In 2013 the genome of the strain A. vancoresmycina
DSM 44592 was sequenced [202]. Vancoresmycin shows minimal inhibitory concentra-
tions against a range of clinically relevant, antibiotic-resistant Gram-positive bacteria. It
selectively targets the cytoplasmic membrane of Gram-positive bacteria via a concentration-
dependent depolarization mechanism [123].
Antibiotics 2021, 10, 1254 16 of 25
6.4. Rifamycin O
Some studies return attention to the natural metabolites of rifampicin, which were not
tested in time due to the establishment of rifampicins B, S, and SV for clinical purposes
(Table 3). In 2020 it was shown that rifamycin O, which is fundamentally different from
other rifamycins in positions C1 and C4, showed significant activity in vitro and in vivo
against M. abscessus. It is the most difficult-to-treat nontuberculous mycobacteria because
of internal and acquired resistance mechanisms and M. abscessus cell wall is 10–20 times
less permeable than that of M. tuberculosis [183].
7. Antibiotics Produced by Amycolatopsis Isolated from Poorly Studied

Ecological Habitats
While metagenomics and high-throughput sequencing tools reveal the species diver-
sity of microbial communities and identify genetic clusters for the production of antibiotics
that have not been detected by cultured approaches, the isolation of a monoculture of
microorganisms is still important for the detection of bioactive compounds. However,
in order to effectively obtain Actinobacteria for the discovery of new drugs, it is neces-
sary to estimate where to search for new producers in terms of geography and specific
ecological systems [203]. The main hopes for new antibiotic discoveries are related to
microorganisms isolated from extreme or unusual environments that are characterized by
challenging conditions such as aridity, high salinity, low nutrient sources, extreme tempera-
tures, and especially the complex composition of microorganism species. Other alternative
promising sources of specialized metabolites are the microbiota of diverse eukaryotic
hosts, including plants, insects, sponges, and humans. The evolution of microorganisms
from such habitats follows a special path, due to geographical and/or genetic isolation
and adaptation to extreme conditions. Therefore, it is likely to find among such endemic
species unique metabolisms, the products of which are new antibiotics. In the last five
years, several new antibiotics produced by various Amycolatopsis strains have been isolated
and described. Most of them are located in special environmental conditions. Recent
studies of lichen-associated Amycolatopsis metabolites have led to the isolation of amycoph-
thalazinone A [44], 2-carbamoyl-3-hydroxy-1,4-naphthoquinone [45], and amycolasporin
C [61]. Amycophthalazinone A is the first example of a naturally occurring phthalazinone
derivative. Amycophthalazinone A exhibits potent inhibitory activity against S. aureus
and Salmonella typhi (MIC 32 µg/mL) [44]. The antimicrobial activity test shows that 2-
carbamoyl-3-hydroxy-1,4-naphthoquinone has significant inhibitory effects on bacterial
pathogens MRSA (MIC 2 µg/mL) and fungal pathogens of Botrytis cinerea and Fusarium
graminearum (MICs 1 µg/mL) [45]. Amycolasporin C shows activity against Bacillus subtilis,
S. aureus, and Escherichia coli (MIC 25 µg/mL) [61]. The sponge-associated marine bacteria
produce more antibiotic substances through competition for space and nutrients. Amy-
colactam, isolated from the A. saalfeldensis, is the bacterial indole alkaloid related to the
cyclopiazonic acid class [32]. The biological activities of amycolactam were evaluated in
antibacterial and antifungal assays against various pathogenic microbes, but the compound
did not exhibit significant inhibitory activities. Amycolactam displays significant cytotoxic-
ity against the gastric cancer cell line and the colon cancer cell line, with IC50 values of 0.8
and 2.0 µM, respectively. Bacteria, through antibiotics, often provide chemical defenses
that selectively inhibit insect microbial competitors and pathogens. Macrotermycins A and
C from the termite-associated Amycolatopsis sp. M39 have antibacterial activity against
human-pathogenic S. aureus (MIC 1.5 and 10 µg/mL, respectively) [14]. Amycolatopsis
sp. HCa4 isolated from the gut of locusts (Locusta migratoria) produces amycolamycin A
which is selectively cytotoxic to the M231 breast cancer cell line [204] and rifamorpholines
A-E [13]. Rifamorpholines represent the new subclass of rifamycin antibiotics with an un-
precedented 5/6/6/6 fused tetracyclic ring system and an unusually modified polyketide
chain. Rifamorpholine B (Figure 3) shows activity against MRSA (MIC 4 µg/mL).
Antibiotics 2021, 10, 1254 17 of 25
8. Conclusions
Medical success in the treatment of many diseases is associated with the development
and widespread use of antibiotics, biologically active substances of natural origin, and
their chemical analogues with antimicrobial, antitumor, antiviral, and immunomodulatory
properties. At the beginning of the birth of the science of antibiotics, which began with
the discovery of penicillin in 1928, the search for new antibiotics has been carried out in a
variety of organisms. Later it was shown that most antibiotics are formed by fungi and
bacteria living in species-enriched biocenoses, primarily in the soil. It was found that the
main producers of antibiotics are actinobacteria. Actinobacteria produce two-thirds of
all known antibiotics used in the clinic today. Among actinobacteria, representatives of
the genus Streptomyces are the champions in a number of identified antibiotics. Unfortu-
nately, at present, the discovery of new natural antibiotics is not as effective as it was in
the “golden era of antibiotics” (1940s–1970s). The study of rare genera of actinobacteria,
which are not as thoroughly studied as Streptomyces, is promising for the search for new
antibiotics. Among such genera, the genus Amycolatopsis is particularly interesting, since
its representatives form antibiotics of different chemical structures, including two espe-
cially important medical antibiotics, vancomycin and rifamycin, and their analogues. The
sequencing of the first complete bacterial genome in 1995 opened a new page of possibil-
ities for antibacterial drug discoverers. The combination of next-generation sequencing
technologies, comparative genomics, and studies of the role of specific gene expression
provides effective opportunities for activating the BGCs that Amycolatopsis is so full of.
Silent BGCs are a treasure trove of potential new antibiotics. An alternative approach to the
search for new antibiotics is to optimize the structural scaffolds with proven antibacterial
activity by genetically engineering strains producing commercially significant antibiotics,
such as A. mediterranei and A. orientalis. Transformation of compounds such as rapamycin
through the application of biosynthetic engineering can deliver novel drug candidates.
Every year, the genus Amycolatopsis opens up new prospects for obtaining new antibiotics.
In the past five years, more than a dozen new antibiotics produced by strains of various
species of Amycolatopsis have been isolated and described. The results of our review show
that members of the genus Amycolatopsis are still a valuable source of new antibiotics, and
our task is to correctly reveal and use this potential.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/10

.3390/antibiotics10101254/s1, Figure S1: Biosynthetic pathway of vancomycin [132,133]. Figure S2:
(A) Biosynthetic pathway of rifamycin B [163,164]. (B) Chemical structure of rifampicin.
Author Contributions: Conceptualization, O.V.E. and O.V.K.; writing—original draft preparation,
O.V.K.; writing—review and editing, T.A.E.; project administration, O.V.E. All authors have read and
agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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Antibiotics-2021-Looking Back To Amycolatopsis

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Antibiotics-2021-Looking Back To Amycolatopsis

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antibiotics

Abstract: The emergence of antibiotic-resistant pathogenic bacteria in recent decades leads us to an

Keywords: antibiotics; antimicrobial compounds; genus Amycolatopsis; glycopeptide antibiotics;

Citation: Kisil, O.V.; Efimenko, T.A.;

Antibiotics 2021, 10, 1254. https://doi.org/10.3390/antibiotics10101254 https://www.mdpi.com/journal/antibiotics

2. The History and Genomic Analysis of Amycolatopsis

Average Total Genome Length Number of Biosynthetic

3. Amycolatopsis Genomic Potential for Antibiotic Production

Species, Strains Antibiotics Properties References

Species, Strains Antibiotics Properties References

Species, Strains Antibiotics Properties References

4.5. Ristocetin (Ristomycin)

4.6. Avoparcin and Emergence of Vancomycin Resistance

vancomycin [149]. Glycopeptide-resistant organisms replace the D-Ala-D-Ala terminus

5.1. Rifamycin’s Discovery and Structure

Z, O, L, Y, etc. Table 3 summarizes the rifamycin derivatives produced by genus Amycolatopsis

Rifamycin Metabolites Possible Precursor Properties References

5.2. Mechanism of Rifampicin Action and Occurrence of Resistance

5.3. Polyketide Backbone Rearrangement

6. Old New Polyenes

6.2. Chelocardin (Otherwise Known as Cetocycline or Cetotetrine)

7. Antibiotics Produced by Amycolatopsis Isolated from Poorly Studied

Supplementary Materials: The following are available online at https://www.mdpi.com/article/10

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