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Design principles to assemble drug combinations for effective tuberculosis therapy using interpretable pairwise drug response measurements.

ABSTRACT: A challenge in tuberculosis treatment regimen design is the necessity to combine three or more antibiotics. We narrow the prohibitively large search space by breaking down high-order drug combinations into drug pair units. Using pairwise in vitro measurements, we train machine learning models to predict higher-order combination treatment outcomes in the relapsing BALB/c mouse model. Classifiers perform well and predict many of the >500 possible combinations among 12 antibiotics to be improved over bedaquiline + pretomanid + linezolid, a treatment-shortening regimen compared with the standard of care in mice. We reformulate classifiers as simple rulesets to reveal guiding principles of constructing combination therapies for both preclinical and clinical outcomes. One example ruleset combines a drug pair that is synergistic in a dormancy model with a pair that is potent in a cholesterol-rich growth environment. These rulesets are predictive, intuitive, and practical, thus enabling rational construction of drug combinations.

SUBMITTER: Larkins-Ford J

PROVIDER: S-EPMC9512659 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Design principles to assemble drug combinations for effective tuberculosis therapy using interpretable pairwise drug response measurements.

Larkins-Ford Jonah J Degefu Yonatan N YN Van Nhi N Sokolov Artem A Aldridge Bree B BB

Cell reports. Medicine 20220908 9

A challenge in tuberculosis treatment regimen design is the necessity to combine three or more antibiotics. We narrow the prohibitively large search space by breaking down high-order drug combinations into drug pair units. Using pairwise in vitro measurements, we train machine learning models to predict higher-order combination treatment outcomes in the relapsing BALB/c mouse model. Classifiers perform well and predict many of the >500 possible combinations among 12 antibiotics to be improved ov ...[more]

PMID: 36084643

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Project description:The treacherous nature of tuberculosis (TB) combined with the ubiquitous presence of the drug-resistant (DR) forms pose this disease as a growing public health menace. Therefore, it is imperative to develop new chemotherapeutic agents with a novel mechanism of action to circumvent the cross-resistance problems. The unique architecture of the Mycobacterium tuberculosis (M. tb) outer envelope plays a predominant role in its pathogenesis, contributing to its intrinsic resistance against available therapeutic agents. The mycobacterial membrane protein large 3 (MmpL3), which is a key player in forging the M. tb rigid cell wall, represents an emerging target for TB drug development. Several indole-2-carboxamides were previously identified in our group as potent anti-TB agents that act as inhibitor of MmpL3 transporter protein. Despite their highly potent in vitro activities, the lingering Achilles heel of these indoleamides can be ascribed to their high lipophilicity as well as low water solubility. In this study, we report our attempt to improve the aqueous solubility of these indole-2-carboxamides while maintaining an adequate lipophilicity to allow effective M. tb cell wall penetration. A more polar adamantanol moiety was incorporated into the framework of several indole-2-carboxamides, whereupon the corresponding analogues were tested for their anti-TB activity against drug-sensitive (DS) M. tb H37Rv strain. Three adamantanol derivatives 8i, 8j and 8l showed nearly 2- and 4-fold higher activity (MIC = 1.32 - 2.89 µM) than ethambutol (MIC = 4.89 µM). Remarkably, the most potent adamantanol analogue 8j demonstrated high selectivity towards DS and DR M. tb strains over mammalian cells [IC50 (Vero cells) ≥ 169 µM], evincing its lack of cytotoxicity. The top eight active compounds 8b, 8d, 8f, 8i, 8j, 8k, 8l and 10a retained their in vitro potency against DR M. tb strains and were docked into the MmpL3 active site. The most potent adamantanol/adamantane-based indoleamides 8j/8k displayed a two-fold surge in potency against extensively DR (XDR) M. tb strains with MIC values of 0.66 and 0.012 µM, respectively. The adamantanol-containing indole-2-carboxamides exhibited improved water solubility both in silico and experimentally, relative to the adamantane counterparts. Overall, the observed antimycobacterial and physicochemical profiles support the notion that adamantanol moiety is a suitable replacement to the adamantane scaffold within the series of indole-2-carboxamide-based MmpL3 inhibitors.

Dataset Information

Design principles to assemble drug combinations for effective tuberculosis therapy using interpretable pairwise drug response measurements.

Publications

Design principles to assemble drug combinations for effective tuberculosis therapy using interpretable pairwise drug response measurements.

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