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A Novel Benzoxaborole Is Active against Escherichia coli and Binds to FabI.

ABSTRACT: To combat the looming crisis of antimicrobial-resistant infections, there is an urgent need for novel antimicrobial discovery and drug target identification. The benzoxaborole series was previously identified as an inhibitor of mycobacterial growth. Here, we demonstrate that a benzoxaborole is also active against the Gram-negative bacterium Escherichia coli in vitro. We isolated resistant mutants of E. coli and subjected them to whole-genome sequencing. We found mutations in the enoyl acyl carrier protein FabI. Mutations mapped around the active center site located close to the cofactor binding site. This site partially overlaps with the binding pocket of triclosan, a known FabI inhibitor. Similar to triclosan, the physical interaction of the benzoxaborole with FabI was dependent on the cofactor NAD⁺. Identification of the putative target of this compound in E. coli provides scope for further development and optimization of this series for Gram-negative pathogens.

SUBMITTER: Mandal S

PROVIDER: S-EPMC8370241 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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A Novel Benzoxaborole Is Active against Escherichia coli and Binds to FabI.

Mandal Soma S Parish Tanya T

Antimicrobial agents and chemotherapy 20210817 9

To combat the looming crisis of antimicrobial-resistant infections, there is an urgent need for novel antimicrobial discovery and drug target identification. The benzoxaborole series was previously identified as an inhibitor of mycobacterial growth. Here, we demonstrate that a benzoxaborole is also active against the Gram-negative bacterium Escherichia coli <i>in vitro</i>. We isolated resistant mutants of E. coli and subjected them to whole-genome sequencing. We found mutations in the enoyl acy ...[more]

PMID: 34152809

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Project description:OBJECTIVES:Drugs for Neglected Diseases initiative (DNDi) has identified three chemical lead series, the nitroimidazoles, benzoxaboroles and aminopyrazoles, as innovative treatments for visceral leishmaniasis. The leads discovered using phenotypic screening, were optimised following disease- and compound-specific criteria. Several leads of each series were progressed and preclinical drug candidates have been nominated. Here we evaluate the efficacy of the lead compounds of each of these three chemical classes in in vitro and in vivo models of cutaneous leishmaniasis. METHODS:The in vitro activity of fifty-five compounds was evaluated against the intracellular amastigotes of L. major, L. aethiopica, L. amazonensis, L. panamensis, L. mexicana and L. tropica. The drugs demonstrating potent activity (EC50 < 5 μM) against at least 4 of 6 species were subsequently evaluated in vivo in different L. major - BALB/c mouse models using a 5 or 10-day treatment with either the oral or topical formulations. Efficacy was expressed as lesion size (measured daily using callipers), parasite load (by quantitative PCR - DNA) and bioluminescence signal reduction relative to the untreated controls. RESULTS:The selected drug compounds (3 nitroimidazoles, 1 benzoxaborole and 3 aminopyrazoles) showed consistent and potent activity across a range of Leishmania species that are known to cause CL with EC50 values ranging from 0.29 to 18.3 μM. In all cases, this potent in vitro antileishmanial activity translated into high levels of efficacy with a linear dose-response against murine CL. When administered at 50 mg/kg/day, DNDI-0690 (nitroimidazole), DNDI-1047 (aminopyrazole) and DNDI-6148 (benzoxaborole) all resulted in a significant lesion size reduction (no visible nodule) and an approximate 2-log-fold reduction of the parasite load as measured by qPCR compared to the untreated control. CONCLUSIONS:The lead compounds DNDI-0690, DNDI-1047 and DNDI-6148 showed excellent activity across a range of Leishmania species in vitro and against L. major in mice. These compounds offer novel potential drugs for the treatment of CL.

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A Novel Benzoxaborole Is Active against Escherichia coli and Binds to FabI.

Publications

A Novel Benzoxaborole Is Active against Escherichia coli and Binds to FabI.

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