Development of 2nd generation aminomethyl spectinomycins that overcome native efflux in Mycobacterium abscessus

Phelps, Gregory A.; Cheramie, Martin N.; Fernando, Dinesh M.; Selchow, Petra; Meyer, Christopher J.; Waidyarachchi, Samanthi L.; Dharuman, Suresh; Liu, Jiuyu; Meuli, Michael; Molin, Michael Dal; Killam, Benjamin Y.; Murphy, Patricia A.; Reeve, Stephanie M.; Wilt, Laura A.; Anderson, Shelby M.; Yang, Lei; Lee, Robin B.; Temrikar, Zaid H.; Lukka, Pradeep B.; Meibohm, Bernd; Polikanov, Yury S.; Hobbie, Sven N.; Böttger, Erik C.; Sander, Peter; Lee, Richard E.

doi:10.1073/pnas.2314101120

Title: Development of 2nd generation aminomethyl spectinomycins that overcome native efflux in Mycobacterium abscessus

Journal Article · 02 January 2024 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.2314101120 · OSTI ID:2470130

^[1]; Cheramie, Martin N. ^[1]; Fernando, Dinesh M. ^[1];

^[2]; Meyer, Christopher J. ^[1];

^[1];

^[3]; Molin, Michael Dal ^[4];

^[5]; Murphy, Patricia A. ^[1]; Reeve, Stephanie M. ^[1];

^[1];

^[1]; Lee, Robin B. ^[1]; Temrikar, Zaid H. ^[6]; Lukka, Pradeep B. ^[6];

^[6] more »

St. Jude Children's Research Hospital, Memphis, TN (United States)
Univ. of Zurich (Switzerland)
Univ. of Zurich (Switzerland); National Reference Center for Mycobacteria, Zurich (Switzerland)
Univ. of Zurich (Switzerland); University Hospital of Cologne (United States)
Univ. of Illinois, Chicago, IL (United States)
Univ. of Tennessee, Knoxville, TN (United States). Health Science Center

Mycobacterium abscessus (Mab), a nontuberculous mycobacterial (NTM) species, is an emerging pathogen with high intrinsic drug resistance. Current standard-of-care therapy results in poor outcomes, demonstrating the urgent need to develop effective antimycobacterial regimens. Through synthetic modification of spectinomycin (SPC), we have identified a distinct structural subclass of N-ethylene linked aminomethyl SPCs (eAmSPCs) that are up to 64-fold more potent against Mab over the parent SPC. Mechanism of action and crystallography studies demonstrate that the eAmSPCs display a mode of ribosomal inhibition consistent with SPC. However, they exert their increased antimicrobial activity through enhanced accumulation, largely by circumventing efflux mechanisms. The N-ethylene linkage within this series plays a critical role in avoiding TetV-mediated efflux, as lead eAmSPC 2593 displays a mere fourfold susceptibility improvement against Mab ΔtetV, in contrast to the 64-fold increase for SPC. Even a minor shortening of the linkage by a single carbon, akin to 1st generation AmSPC 1950, results in a substantial increase in MICs and a 16-fold rise in susceptibility against Mab ΔtetV. These shifts suggest that longer linkages might modify the kinetics of drug expulsion by TetV, ultimately shifting the equilibrium towards heightened intracellular concentrations and enhanced antimicrobial efficacy. Furthermore, lead eAmSPCs were also shown to synergize with various classes of anti-Mab antibiotics and retain activity against clinical isolates and other mycobacterial strains. Encouraging pharmacokinetic profiles coupled with robust efficacy in Mab murine infection models suggest that eAmSPCs hold the potential to be developed into treatments for Mab and other NTM infections.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Cancer Institute (NCI); National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2470130

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 2 Vol. 121; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
antibiotic
antimicrobial resistance
efflux
nontuberculous mycobacteria
protein synthesis inhibitor

Title: Development of 2nd generation aminomethyl spectinomycins that overcome native efflux in Mycobacterium abscessus

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