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Structure-Activity Relationship of Anti-Mycobacterium abscessus Piperidine-4-carboxamides, a New Class of NBTI DNA Gyrase Inhibitors.

ABSTRACT: Mycobacterium abscessus causes difficult-to-cure pulmonary infections. The bacterium is resistant to most anti-infective agents, including first line antituberculosis (anti-TB) drugs. MMV688844 (844) is a piperidine-4-carboxamide (P4C) with bactericidal properties against M. abscessus. We recently identified DNA gyrase as the molecular target of 844. Here, we present in silico docking and genetic evidence suggesting that P4Cs display a similar binding mode to DNA gyrase as gepotidacin. Gepotidacin is a member of the Novel Bacterial Topoisomerase Inhibitors (NBTIs), a new class of nonfluoroquinolone DNA gyrase poisons. Thus, our work suggests that P4Cs present a novel structural subclass of NBTI. We describe structure-activity relationship studies of 844 leading to analogues showing increased antibacterial activity. Selected derivatives were tested for their inhibitory activity against recombinant M. abscessus DNA gyrase. Further optimization of the lead structures led to improved stability in mouse plasma and increased oral bioavailability.

SUBMITTER: Beuchel A

PROVIDER: S-EPMC8919391 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Structure-Activity Relationship of Anti-Mycobacterium abscessus Piperidine-4-carboxamides, a New Class of NBTI DNA Gyrase Inhibitors.

Beuchel Andreas A Robaa Dina D Negatu Dereje A DA Madani Abdeldjalil A Alvarez Nadine N Zimmerman Matthew D MD Richter Adrian A Mann Lea L Hoenke Sophie S Csuk René R Dick Thomas T Imming Peter P

ACS medicinal chemistry letters 20220228 3

Mycobacterium abscessus causes difficult-to-cure pulmonary infections. The bacterium is resistant to most anti-infective agents, including first line antituberculosis (anti-TB) drugs. MMV688844 (844) is a piperidine-4-carboxamide (P4C) with bactericidal properties against M. abscessus. We recently identified DNA gyrase as the molecular target of 844. Here, we present in silico docking and genetic evidence suggesting that P4Cs display a similar binding mode to D ...[more]

PMID: 35300094

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Project description:Treatment options for human cytomegalovirus (CMV) remain limited and are associated with significant adverse effects and the selection of resistant CMV strains in transplant recipients and congenitally infected infants. Although most approved drugs target and inhibit the CMV DNA polymerase, additional agents with distinct mechanisms of action are needed for the treatment and prevention of CMV. In a large high throughput screen using our CMV-luciferase reporter Towne, we identified several unique inhibitors of CMV replication. Here, we synthesize and test in vitro 13 analogs of the original NCGC2955 hit (1). Analogs with no activity against the CMV-luciferase at 10 µM and 30 µM (2-6, 10-14) were removed from further analysis. Three analogs (7-9) inhibited CMV replication in infected human foreskin fibroblasts. The EC50 of (1) was 1.7 ± 0.6 µM and 1.99 ± 0.15 µM, based on luciferase and plaque assay, respectively. Compounds 7, 8, and 9 showed similar activities: the EC50 values of 7 were 0.21 ± 0.06 µM (luciferase) and 0.55 ± 0.06 (plaque), of 8: 0.28 ± 0.06 µM and 0.42 ± 0.07, and of 9: 0.30 ± 0.05 µM (luciferase) and 0.35 ± 0.07 (plaque). The CC50 for 7, 8, and 9 in non-infected human foreskin fibroblasts was > 500µM, yielding a selectivity index of >1500. Compounds 1, 7, and 8 were also tested in CMV-infected primary human hepatocytes and showed a dose-response against CMV by luciferase activity and viral protein expression. None of the active compounds inhibited herpes simplex virus 1 or 2. Compounds 7 and 8 inhibited mouse CMV replication in vitro. Both inhibited CMV at late stages of replication; 7 reduced virus yield at all late time points, although not to the same degree as letermovir. Finally, the activity of analog 8 was additive with newly identified CMV inhibitors (MLS8969, NFU1827, MSL8554, and MSL8091) and with ganciclovir. Further structural activity development should provide promising anti-CMV agents for use in clinical studies.

Project description:The aminobenzimidazole SPR719 targets DNA gyrase in Mycobacterium tuberculosis. The molecule acts as inhibitor of the enzyme's ATPase located on the Gyrase B subunit of the tetrameric Gyrase A2B2 protein. SPR719 is also active against non-tuberculous mycobacteria (NTM) and recently entered clinical development for lung disease caused by these bacteria. Resistance against SPR719 in NTM has not been characterized. Here, we determined spontaneous in vitro resistance frequencies in single step resistance development studies, MICs of resistant strains, and resistance associated DNA sequence polymorphisms in two major NTM pathogens Mycobacterium avium and Mycobacterium abscessus. A low-frequency resistance (10-8/CFU) was associated with missense mutations in the ATPase domain of the Gyrase B subunit in both bacteria, consistent with inhibition of DNA gyrase as the mechanism of action of SPR719 against NTM. For M. abscessus, but not for M. avium, a second, high-frequency (10-6/CFU) resistance mechanism was observed. High-frequency SPR719 resistance was associated with frameshift mutations in the transcriptional repressor MAB_4384 previously shown to regulate expression of the drug efflux pump system MmpS5/MmpL5. Our results confirm DNA gyrase as target of SPR719 in NTM and reveal differential resistance development in the two NTM species, with M. abscessus displaying high-frequency indirect resistance possibly involving drug efflux. IMPORTANCE Clinical emergence of resistance to new antibiotics affects their utility. Characterization of in vitro resistance is a first step in the profiling of resistance properties of novel drug candidates. Here, we characterized in vitro resistance against SPR719, a drug candidate for the treatment of lung disease caused by non-tuberculous mycobacteria (NTM). The identified resistance associated mutations and the observed differential resistance behavior of the two characterized NTM species provide a basis for follow-up studies of resistance in vivo to further inform clinical development of SPR719.

Dataset Information

Structure-Activity Relationship of Anti-Mycobacterium abscessus Piperidine-4-carboxamides, a New Class of NBTI DNA Gyrase Inhibitors.

Publications

Structure-Activity Relationship of Anti-<i>Mycobacterium abscessus</i> Piperidine-4-carboxamides, a New Class of NBTI DNA Gyrase Inhibitors.

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