Papers by Dr. Tridib Chaira
Antimicrobial Agents and Chemotherapy, Apr 1, 2018
The emergence of multidrug-resistant (MDR) Gram-negative bacilli is a major concern in the treatm... more The emergence of multidrug-resistant (MDR) Gram-negative bacilli is a major concern in the treatment of nosocomial infections. Antibacterial agents with novel modes of action can be useful, as these pathogens have become resistant to almost all existing standard-of-care agents. GSK2251052, a leucyl-tRNA synthetase inhibitor, has a novel mode of action against Gram-negative bacteria. However, the phase 2 studies with this drug were terminated due to microbiological failures based on the rapid emergence of drug resistance during the treatment of complicated urinary tract infections. DS86760016 is a novel leucyl-tRNA synthetase inhibitor active against MDR Gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, with an improved pharmacokinetic profile. DS86760016 showed lower plasma clearance, longer plasma half-life, and higher renal excretion than GSK2251052 did in mice, rats, monkeys and dogs. DS86760016 also showed lower mutant prevention concentrations against P. aeruginosa than did GSK2251052. No resistant bacteria were observed in murine urinary tract infection models at a dose that maintained urinary concentrations above the mutant prevention concentration. DS86760016 also showed a lower risk of resistance development than did GSK2251052 in comparative in vivo studies with murine urinary tract infection models. These results suggest that DS86760016 has potential as a new drug for the treatment of MDR Gram-negative bacterial infections, with a lower risk of drug resistance development than that of GSK2251052.
Pharmaceutics, Apr 11, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
bioRxiv (Cold Spring Harbor Laboratory), Sep 8, 2022
Development of a novel inhibitor targeting Gyrase B and Topoisomerase IV offers a potential oppor... more Development of a novel inhibitor targeting Gyrase B and Topoisomerase IV offers a potential opportunity to combat the drug resistance. In the present study, we extensively investigated the efficacy of RBx 10080758, a novel fluorobenzothiazole, against skin and respiratory infections caused by Staphylococci and Streptococci in in vitro and in vivo models. RBx 10080758 showed a potent IC 50 of 0.06 µM against Gyrase and Topoisomerase IV and also exhibited a strong whole cell in vitro activity with MIC ranges of 0.
Journal of Antimicrobial Chemotherapy, May 2, 2019
BACKGROUND RBx 14255 is a fluoroketolide in pre-clinical evaluation with potent activity against ... more BACKGROUND RBx 14255 is a fluoroketolide in pre-clinical evaluation with potent activity against MDR Gram-positive pathogens. OBJECTIVES To investigate the efficacy of RBx 14255 against bacterial meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis or Haemophilus influenzae in an experimental murine meningitis model. METHODS In vitro activity of RBx 14255 was evaluated against clinical isolates of S. pneumoniae, N. meningitidis and H. influenzae. The in vivo efficacy of RBx 14255 was evaluated against bacterial meningitis, induced with S. pneumoniae 3579 erm(B), S. pneumoniae MA 80 erm(B), N. meningitidis 1852 and H. influenzae B1414 in a murine meningitis model. RESULTS RBx 14255 showed strong in vitro bactericidal potential against S. pneumoniae, N. meningitidis and H. influenzae with MIC ranges of 0.004-0.1, 0.03-0.5 and 1-4 mg/L, respectively. In a murine meningitis model, a 50 mg/kg dose of RBx 14255, q12h, resulted in significant reduction of bacterial counts in the brain compared with the pretreatment control. The concentration of RBx 14255 in brain tissue correlated well with the efficacy in this mouse model. CONCLUSIONS RBx 14255 showed superior bactericidal activity in time-kill assays in vitro and in vivo in an experimental murine meningitis model. RBx 14255 could be a promising candidate for future drug development against bacterial meningitis.
Frontiers in Microbiology, Apr 23, 2021
Pseudomonas aeruginosa forms biofilms in the lungs of chronically infected cystic fibrosis patien... more Pseudomonas aeruginosa forms biofilms in the lungs of chronically infected cystic fibrosis patients, which are tolerant to both the treatment of antibiotics and the host immune system. Normally, antibiotics are less effective against bacteria growing in biofilms; azithromycin has shown a potent efficacy in cystic fibrosis patients chronically infected with P. aeruginosa and improved their lung function. The present study was conducted to evaluate the effect of azithromycin on P. aeruginosa biofilm. We show that azithromycin exhibited a potent activity against P. aeruginosa biofilm, and microscopic observation revealed that azithromycin substantially inhibited the formation of solid surface biofilms. Interestingly, we observed that azithromycin restricted P. aeruginosa biofilm formation by inhibiting the expression of pel genes, which has been previously shown to play an essential role in bacterial attachment to solid-surface biofilm. In a rat model of chronic P. aeruginosa lung infection, we show that azithromycin treatment resulted in the suppression of quorum sensing-regulated virulence factors, significantly improving the clearance of P. aeruginosa biofilms compared to that in the placebo control. We conclude that azithromycin attenuates P. aeruginosa biofilm formation, impairs its ability to produce extracellular biofilm matrix, and increases its sensitivity to the immune system, which may explain the clinical efficacy of azithromycin in cystic fibrosis patients.
Antimicrobial Agents and Chemotherapy, Apr 1, 2019
DS86760016 is a new leucyl-tRNA-synthetase inhibitor at the preclinical development stage. DS8676... more DS86760016 is a new leucyl-tRNA-synthetase inhibitor at the preclinical development stage. DS86760016 showed potent activity against extendedspectrum multidrug-resistant Pseudomonas aeruginosa isolated from clinical samples and in vitro biofilms. In a murine catheter-associated urinary tract infection model, DS86760016 treatment resulted in significant eradication of P. aeruginosa from the kidney, bladder, and catheter without developing drug resistance. Our data suggest that DS86760016 has the potential to act as a new drug for the treatment of Pseudomonas infections.
Current Drug Discovery Technologies, Sep 1, 2010
There have been major strides in the development of novel ways of investigating drug like propert... more There have been major strides in the development of novel ways of investigating drug like properties of new chemical entities (NCE) in the last three decades. Identification of ideal properties of a clinical candidate that would give a clinical proof of concept (POC) is the most critical step in the discovery process. Besides the biological dose-response relationship, the pharmacokinetic parameters play the most vital role in influencing the therapeutic response or toxicity of NCE. While there are numerous techniques to understand various drug-like properties individually, the behavior of an NCE in a dynamic in vivo system which influences its therapeutic or toxic effects is a composite function of its various physicochemical and pharmacokinetic parameters. This implies the need to understand the collective influence of various measured parameters, and knowing how variations made in them can result in favorable pharmacodynamic or toxicokinetic properties. Understanding this behavior holds the key to a successful and time efficient lead optimization process. Physiological based pharmacokinetic models (PBPK) are of great interest in this context as they involve a natural way of integrating the individual compound property to physiological properties, providing a rational approach to predict drug like behavior (an ideal behavior identified may be addressed generally as Target Product Profile) in vivo. In the current review, various physiological pharmacokinetic models addressing absorption, tissue distribution and clearance are discussed along with their application in integrating various physicochemical and ADME parameters to predict human pharmacokinetics helping lead optimization.
Future Microbiology
Aim: The development of a novel inhibitor targeting gyrase B and topoisomerase IV offers an oppor... more Aim: The development of a novel inhibitor targeting gyrase B and topoisomerase IV offers an opportunity to combat multidrug resistance. Methods: We investigated the activity of RBx 10080758 against Gram-positive bacteria in vitro and in vivo. Results: RBx 10080758 showed a potent 50% inhibitory concentration of 0.13 μM and 0.25 μM against gyrase B and topoisomerase IV, respectively, and exhibited strong whole-cell in vitro activity with MIC ranges of 0.015–0.06 and 0.015–0.03 μg/ml against Staphylococcus aureus and Streptococcus pneumoniae, respectively. In a rat thigh infection model with methicillin-resistant S. aureus, RBx 10080758 at 45 mg/kg exhibited a >3 log10 CFU reduction in thigh muscles. Conclusion: RBx 10080758 displayed potent activity against multiple multidrug-resistant Gram-positive bacteria with a dual-targeting mechanism of action.
Pharmaceutics
The search for new drugs is an extremely time-consuming and expensive endeavour. Much of that tim... more The search for new drugs is an extremely time-consuming and expensive endeavour. Much of that time and money go into generating predictive human pharmacokinetic profiles from preclinical efficacy and safety animal data. These pharmacokinetic profiles are used to prioritize or minimize the attrition at later stages of the drug discovery process. In the area of antiviral drug research, these pharmacokinetic profiles are equally important for the optimization, estimation of half-life, determination of effective dose, and dosing regimen, in humans. In this article we have highlighted three important aspects of these profiles. First, the impact of plasma protein binding on two primary pharmacokinetic parameters—volume of distribution and clearance. Second, interdependence of primary parameters on unbound fraction of the drug. Third, the ability to extrapolate human pharmacokinetic parameters and concentration time profiles from animal profiles.
Journal of Antimicrobial Chemotherapy
Objectives FtsZ is an essential bacterial protein and an unexplored target for the development of... more Objectives FtsZ is an essential bacterial protein and an unexplored target for the development of antibacterial drugs. The development of a novel inhibitor targeting FtsZ offers a potential opportunity to combat drug resistance. DS01750413, a new derivative of PC190723, is a novel FtsZ inhibitor with improved in vitro and in vivo activity. The objective of this study was to investigate the efficacy of DS01750413 against Staphylococcus spp., including MRSA, in in vitro and in vivo models. Methods In vitro activities of DS01750413 and standard-of-care antibiotics were evaluated against clinical isolates of Gram-positive pathogens. The in vivo efficacy was evaluated in a murine systemic infection model caused by MRSA. Results DS01750413 showed potent in vitro activity against MRSA clinical isolates with MIC ranges of 0.5–1 mg/L and also demonstrated concentration-dependent bactericidal killing. In the murine bacteraemia infection model of MRSA, treatment with DS01750413 resulted in pro...
Development of a novel inhibitor targeting Gyrase B and Topoisomerase IV offers a potential oppor... more Development of a novel inhibitor targeting Gyrase B and Topoisomerase IV offers a potential opportunity to combat the drug resistance. In the present study, we extensively investigated the efficacy of RBx 10080758, a novel fluorobenzothiazole, against skin and respiratory infections caused by Staphylococci and Streptococci in in vitro and in vivo models. RBx 10080758 showed a potent IC50 of 0.06 μM against Gyrase and Topoisomerase IV and also exhibited a strong whole cell in vitro activity with MIC ranges of 0.015-0.06, 0.015-0.03, 0.008-0.03, 0.008-0.03, 0.008-0.0.06, 0.015-0.06 μg/ml against Staphylococcus. aureus, Streptococcus pneumoniae, Coagulase negative Staphylococci, Streptococcus viridans, Streptococcus pyogenes and Enterococcus, respectively. As expected from the novel class of molecule, it retains potent even against linezolid and vancomycin resistant strains. Interesting, in mouse systemic infection 10 mg/kg, IV dose protected 100% mice from lethal infections. In rat th...
Frontiers in Microbiology, 2021
Pseudomonas aeruginosaforms biofilms in the lungs of chronically infected cystic fibrosis patient... more Pseudomonas aeruginosaforms biofilms in the lungs of chronically infected cystic fibrosis patients, which are tolerant to both the treatment of antibiotics and the host immune system. Normally, antibiotics are less effective against bacteria growing in biofilms; azithromycin has shown a potent efficacy in cystic fibrosis patients chronically infected withP. aeruginosaand improved their lung function. The present study was conducted to evaluate the effect of azithromycin onP. aeruginosabiofilm. We show that azithromycin exhibited a potent activity againstP. aeruginosabiofilm, and microscopic observation revealed that azithromycin substantially inhibited the formation of solid surface biofilms. Interestingly, we observed that azithromycin restrictedP. aeruginosabiofilm formation by inhibiting the expression ofpelgenes, which has been previously shown to play an essential role in bacterial attachment to solid-surface biofilm. In a rat model of chronicP. aeruginosalung infection, we sho...
Current Drug Delivery, 2020
Background: Rifampicin is known to degrade at the acidic pH of the stomach, especially in the pre... more Background: Rifampicin is known to degrade at the acidic pH of the stomach, especially in the presence of isoniazid. Although isoniazid also degrades partially, its degradation is reversible. Objective: Presently, we provide a proof of the fact that the simultaneous oral administration of rifampicin (RIF), upon incorporation into solid lipid nanoparticles (RIF-SLNs), with isoniazid (INH) overcomes its INH-induced degradation and improves its oral bioavailability in rats. Methods: Solid lipid nanoparticles of RIF (RIF-SLNs) were prepared using a novel and patented method. The effect of INH was investigated on in vivo bioavailability of RIF both in its free and encapsulated (RIF-SLNs) form, after oral administration to rats. Results: Cmax and AUC0-∞ of RIF increased 158 % and 125 %, respectively, upon incorporation into SLNs versus free RIF when combined with INH. The Tmax decreased from 5.67 h to 3.3 h, and the plasma concentration of RIF remained above its MIC (8 μg/ml) at all the t...
Antimicrobial Agents and Chemotherapy, 2019
Indole-2-carboxamide derivatives are inhibitors of MmpL3, the cell wall-associated mycolic acid t... more Indole-2-carboxamide derivatives are inhibitors of MmpL3, the cell wall-associated mycolic acid transporter of Mycobacterium tuberculosis . In the present study, we characterized indoleamide effects on bacterial cell morphology and reevaluated pharmacokinetics and in vivo efficacy using an optimized oral formulation.
Antimicrobial Agents and Chemotherapy, 2018
The emergence of multidrug-resistant (MDR) Gram-negative bacilli is a major concern in the treatm... more The emergence of multidrug-resistant (MDR) Gram-negative bacilli is a major concern in the treatment of nosocomial infections. Antibacterial agents with novel modes of action can be useful, as these pathogens have become resistant to almost all existing standard-of-care agents. GSK2251052, a leucyl-tRNA synthetase inhibitor, has a novel mode of action against Gram-negative bacteria. However, the phase 2 studies with this drug were terminated due to microbiological failures based on the rapid emergence of drug resistance during the treatment of complicated urinary tract infections. DS86760016 is a novel leucyl-tRNA synthetase inhibitor active against MDR Gram-negative bacteria, such as Escherichia coli , Klebsiella pneumoniae , and Pseudomonas aeruginosa , with an improved pharmacokinetic profile. DS86760016 showed lower plasma clearance, longer plasma half-life, and higher renal excretion than GSK2251052 did in mice, rats, monkeys and dogs. DS86760016 also showed lower mutant preven...
Antimicrobial Agents and Chemotherapy, 2019
DS86760016 is a new leucyl-tRNA-synthetase inhibitor at the preclinical development stage. DS8676... more DS86760016 is a new leucyl-tRNA-synthetase inhibitor at the preclinical development stage. DS86760016 showed potent activity against extended-spectrum multidrug-resistant Pseudomonas aeruginosa isolated from clinical samples and in vitro biofilms.
Bioorganic & medicinal chemistry letters, Jan 12, 2018
FimH is a type I fimbrial lectin located at the tip of type-1 pili of Gram-negative uropathogenic... more FimH is a type I fimbrial lectin located at the tip of type-1 pili of Gram-negative uropathogenic Escherichia coli (UPEC) guiding its ability to adhere and infect urothelial cells. Accordingly, blocking FimH with small molecule inhibitor is considered as a promising new therapeutic alternative to treat urinary tract infections caused by UPEC. Herein, we report that compounds having the S-glycosidic bond (thiomannosides) had improved metabolic stability and plasma exposures when dosed orally. Especially compound 5h showed the potential to inhibit biofilm formation and also to disrupt the preformed biofilm. And compound 5h showed prophylactic effect in UTI model in mice.
Nanomedicine : nanotechnology, biology, and medicine, Jan 7, 2018
RBx 11,760 is a bi-aryl oxazolidinone antibacterial agent active against Staphylococcus aureus bu... more RBx 11,760 is a bi-aryl oxazolidinone antibacterial agent active against Staphylococcus aureus but has poor solubility. Here we have encapsulated RBx 11,760 in PLA-PEG NPs with an aim to improve physicochemical, pharmacokinetics and in vivo efficacy. The average size and zeta potential of RBx 11,760 loaded NPs were found to be 106.4 nm and -22.2 mV, respectively. The absolute size of nanoparticles by HRTEM was found to be approximately 80 nm. In vitro antibacterial agar well diffusion assay showed clear zone of inhibition of bacterial growth. In pharmacokinetic study, nanoparticle showed 4.6-fold and 7-fold increase in AUCand half-life, respectively, as compared to free drug. RBx 11,760 nanoparticle significantly reduced bacterial counts in lungs and improved the survival rate of immunocompromised mice as compared to free drugs. Thus, RBx 11,760 loaded nanoparticles have strong potential to be used as nanomedicine against sensitive and drug resistant Staphylococcus aureus infections.
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Antimicrobial agents and chemotherapy, Jan 12, 2018
DS-2969b is a novel GyrB inhibitor, which is currently under clinical development for treatment o... more DS-2969b is a novel GyrB inhibitor, which is currently under clinical development for treatment ofinfection (CDI). In this study, theandactivities of DS-2969b were evaluated. DS-2969b inhibited the supercoiling activity ofDNA gyrase. DS-2969b showed potentactivity againstclinical isolates with an MICof 0.06 μg/mL, which was 2-, 32-, and 16-fold lower than the MICof fidaxomicin, vancomycin, and metronidazole, respectively. DS-2969b did not select spontaneous resistant mutant of variousstrains at 4 × MICs and the frequency of resistance development was less than 4.8 × 10In a hamster CDI model, 5-day oral administration of DS-2969b conferred complete protection from recurrence and mortality at 0.3 mg/kg once a day compared with 50% survival rate with fidaxomicin at 3 mg/kg once a day and 0% with vancomycin at 50 mg/kg/dose twice a day. Even a single oral administration of 1 mg/kg of DS-2969b in the CDI model exhibited 100% animal survival without recurrence. DS-2969b was also efficacio...
Journal of medicinal chemistry, Jan 2, 2017
Mycobacterium abscessus is a fast-growing, multidrug-resistant organism that has emerged as a cli... more Mycobacterium abscessus is a fast-growing, multidrug-resistant organism that has emerged as a clinically significant pathogen in cystic fibrosis (CF) patients. The intrinsic resistance of M. abscessus to most commonly available antibiotics seriously restricts chemotherapeutic options. Herein, we report the potent activity of a series of indolecarboxamides against M. abscessus. The lead compounds, 6 and 12, exhibited strong activity in vitro against a wide panel of M. abscessus isolates and in infected macrophages. High resistance levels to the indolecarboxamides appear to be associated with an A309P mutation in the mycolic acid transporter MmpL3. Biochemical analyses demonstrated that while de novo mycolic acid synthesis remained unaffected, the indolecarboxamides strongly inhibited the transport of trehalose monomycolate, resulting in the loss of trehalose dimycolate production and abrogating mycolylation of arabinogalactan. Our data introduce a hereto unexploited chemical structur...
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Papers by Dr. Tridib Chaira