Biology subjects

Sarathy, J. P.

Publications and source records attributed to Sarathy, J. P..

5 recordsLinked to original sources

bioRxiv2026

Comprehensive preclinical reevaluation of PaBQU and DBQU regimens identifies lesional liability in hard-to-treat forms of tuberculosis

Murine efficacy models inform advancement of preclinical tuberculosis treatment regimens to human clinical testing. A recent human Phase 2 trial was terminated early because investigational regimens (4-months of PaBQU or DBQU) did not meet the treatment shortening criteria outlined in the Target Regimen Profile ([≤] 3 months). We queried whether a factor leading to this early termination may have been lesional liability, meaning slow or diminished onset of effect in the caseum of complex lung lesions. We conducted a translational study, comparing the easy-to-treat BALB/c mouse, lacking complex lesions, to the hard-to-treat C3HeB/FeJ mouse that develops complex human-like lesions. We evaluated traditional and novel pharmacodynamic markers (colony forming units and RS ratio), relapse outcomes and ex vivo caseum pharmacokinetics. PaBQU and DBQU were slower to elicit bactericidal activity, RS ratio activity and prevent relapse in the C3HeB/FeJ mouse than the BALB/c mouse. A reference regimen (BPaMZ) had less lesional liability than PaBQU and DBQU. Fewer drugs in PaBQU were projected to achieve target attainment in caseum compared to BPaMZ, particularly early in treatment due to slow accumulation of bedaquiline in caseum. Here, we demonstrated application of a multi-modality pharmacokinetic-pharmacodynamic analysis that compared regimen activity in the hard-to-treat C3HeB/FeJ and easy-to-treat BALB/c mouse models, identifying lesional liability of PaBQU and DBQU. Systematic interrogation of additional diverse regimens is needed to determine the value of preclinical lesional liability as a means of predicting clinical treatment shortening activity.

microbiology↗

bioRxiv2024

Contribution of front-line, standard of care drugs to bactericidal responses, resistance emergence, and cure in murine models of easy- or hard-to-treat tuberculosis disease

By assessing the standard of care regimen for tuberculosis (TB) in BALB/c and C3HeB/FeJ mice, we demonstrate that rifampin, with or without pyrazinamide, is essential to effective bactericidal response and resistance suppression. Potency measurements in an in vitro lipid-rich model and rabbit caseum assay recapitulate the significance of rifampin as a sterilizing agent. These outcomes align with clinical performance, thus emphasizing the value of in vitro predictive tools and murine TB models with human-like pathology.

microbiology↗

bioRxiv2024

Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis

The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis. Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. To demonstrate that this translates to more effective cure, we first confirmed the role of rifampin, with or without pyrazinamide, as essential to achieve effective bactericidal responses and sterilizing cure in the current standard of care regimen in chronically infected C3HeB/FeJ mice compared to BALB/c mice. Thus, demonstrating added value in testing clinically relevant regimens in murine models of increasing pathologic complexity. Next we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models including mice exhibiting advanced pulmonary disease can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.

microbiology↗

bioRxiv2023

Lung microenvironments harbor Mycobacterium tuberculosis phenotypes with distinct treatment responses

Tuberculosis lung lesions are complex and harbor heterogeneous microenvironments that influence antibiotic effectiveness. Major strides have been made recently in understanding drug pharmacokinetics in pulmonary lesions, but the bacterial phenotypes that arise under these conditions and their contribution to drug tolerance is poorly understood. A pharmacodynamic marker called the RS ratio quantifies ongoing rRNA synthesis based on the abundance of newly-synthesized precursor rRNA relative to mature structural rRNA. Application of the RS ratio in the C3HeB/FeJ mouse model demonstrated that Mycobacterium tuberculosis populations residing in different tissue microenvironments are phenotypically distinct and respond differently to drug treatment with rifampin, isoniazid or bedaquiline. This work provides a foundational basis required to address how anatomic and pathologic microenvironmental niches may contribute to the long treatment duration and drug tolerance during treatment of human tuberculosis.

microbiology↗

bioRxiv2022

Mycobacterium tuberculosis DprE1 inhibitor OPC-167832 is active against Mycobacterium abscessus in vitro

The anti-tuberculosis candidate OPC-167832, an inhibitor of DprE1, was active against Mycobacterium abscessus. Resistance mapped to M. abscessus dprE1, suggesting target retention. OPC-167832 was bactericidal and did not antagonize activity of clinical anti-M. abscessus antibiotics. Due to its moderate potency compared to Mycobacterium tuberculosis, the compound lacked efficacy in a mouse model and is thus not a repurposing candidate. These results identify OPC-167832 - DprE1 as a lead-target couple for a M. abscessus-specific optimization program.

microbiology↗