Biology subjects

Poonawala, H.

Publications and source records attributed to Poonawala, H..

2 recordsLinked to original sources

bioRxiv2025

Antibiotic dose-response curves can measure antibiotic activity against Mycobacterium abscessus and Mycobacterium peregrinum

Mycobacterium abscessus is a drug-resistant pathogen associated with poor clinical outcomes despite treatment with multidrug antibiotic regimens. Apart from clarithromycin, antimicrobial susceptibility testing (AST) results for Mycobacterium abscessus cannot guide antibiotic selection. AST involves measuring the minimum inhibitory concentration (MIC), which is allowed to span a four-fold range in concentration. This accepted variability of the MIC limits the clinical utility of AST. Antimicrobial dose-response curves, obtained by measuring the growth inhibition of a given organism to increasing concentrations of an antibiotic, can yield metrics of antibiotic activity that are less variable than the MIC. We used Clinical and Laboratory Standards Institute growth conditions for rapid-grower nontuberculous mycobacteria to generate 990 dose-response curves across three time points (72 hours, 96 hours, and 120 hours) for six guideline-recommended (clarithromycin, amikacin, cefoxitin, linezolid, tigecycline, and clofazimine) and five new (omadacycline, tedizolid, SPR719, SQ109, and bedaquiline) antibiotics against Mycobacterium abscessus subspecies abscessus ATCC 19977 and Mycobacterium peregrinum ATCC 700686. We established the fit of the dose-response curve (R2) as a quality control metric. Using the geometric standard deviation and median coefficient of variation, we demonstrated that the IC50 and IC75 (antibiotic concentrations corresponding to 50% and 75% growth inhibition, respectively) are less variable than the MIC. We identified time-dependent changes in dose-response curve metrics that allow the detection of inducible clarithromycin resistance with only five days of incubation. This study demonstrates the potential of dose-response curves in measuring antibiotic activity against Mycobacterium abscessus.

microbiology↗

bioRxiv2022

Novel synergies and isolate specificities in the drug interactions landscape of Mycobacterium abscessus

Mycobacterium abscessus infections are difficult to treat and are often considered untreatable without tissue resection. Due to the intrinsic drug-resistant nature of the bacteria, combination therapy of three or more antibiotics is recommended. A major challenge in treating M. abscessus infections is the absence of a universal combination therapy with satisfying clinical success rates, leaving clinicians to treat infections using antibiotic lacking efficacy data. We systematically measured drug combinations in M. abscessus to establish a resource of drug interaction data and identify patterns of synergy to help design optimized combination therapies. We measured approximately 230 pairwise drug interactions among 22 antibiotics and identified 71 synergistic pairs, 54 antagonistic pairs, and four potentiator-antibiotics not previously reported. We found that commonly used drug combinations in the clinic, such as azithromycin and amikacin, are antagonistic in lab reference strain ATCC19977, whereas novel combinations, such as azithromycin and rifampicin, are synergistic. Another challenge in developing universally effective multidrug therapies for M. abscessus is the significant variation in drug response between isolates. We measured drug interactions in a focused set of 36 drug pairs across a small panel of clinical isolates with rough and smooth morphotypes. We observed highly strain-dependent drug interactions that cannot be predicted from single-drug susceptibility profiles or known drug mechanisms of action. Our study demonstrates the immense potential to identify synergistic drug combinations in the vast drug combination space and emphasizes the importance of strain-specific combination measurements for designing improved therapeutic interventions.

microbiology↗