Synthetic oxepanoprolinamide iboxamycin is active against Listeria monocytogenes despite the intrinsic resistance mediated by VgaL/Lmo0919 ABCF ATPase

Tetiana Brodiazhenko; Kathryn Jane Turnbull; Kelvin J Y Wu; Hiraku Takada; Ben I C Tresco; Tanel Tenson; Andrew G Myers; Vasili Hauryliuk

doi:10.1093/jacamr/dlac061

Synthetic oxepanoprolinamide iboxamycin is active against Listeria monocytogenes despite the intrinsic resistance mediated by VgaL/Lmo0919 ABCF ATPase

JAC Antimicrob Resist. 2022 Jun 17;4(3):dlac061. doi: 10.1093/jacamr/dlac061. eCollection 2022 Jun.

Authors

Tetiana Brodiazhenko¹, Kathryn Jane Turnbull², Kelvin J Y Wu³, Hiraku Takada⁴, Ben I C Tresco³, Tanel Tenson¹, Andrew G Myers³, Vasili Hauryliuk¹

Affiliations

¹ University of Tartu, Institute of Technology, 50411 Tartu, Estonia.
² Department of Clinical Microbiology, Rigshospitalet, 2200 Copenhagen, Denmark.
³ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
⁴ Department of Experimental Medicine, University of Lund, 221 84 Lund, Sweden.

Abstract

Background: Listeriosis is a food-borne disease caused by the Gram-positive Bacillota (Firmicute) bacterium Listeria monocytogenes. Clinical L. monocytogenes isolates are often resistant to clinically used lincosamide clindamycin, thus excluding clindamycin as a viable treatment option.

Objectives: We have established newly developed lincosamide iboxamycin as a potential novel antilisterial agent.

Methods: We determined MICs of the lincosamides lincomycin, clindamycin and iboxamycin for L. monocytogenes, Enterococcus faecalis and Bacillus subtilis strains expressing synergetic antibiotic resistance determinants: ABCF ATPases that directly displace antibiotics from the ribosome and Cfr, a 23S rRNA methyltransferase that compromises antibiotic binding. For L. monocytogenes strains, either expressing VgaL/Lmo0919 or lacking the resistance factor, we performed time-kill kinetics and post-antibiotic effect assays.

Results: We show that the synthetic lincosamide iboxamycin is highly active against L. monocytogenes and can overcome the intrinsic lincosamide resistance mediated by VgaL/Lmo0919 ABCF ATPase. While iboxamycin is not bactericidal against L. monocytogenes, it displays a pronounced post-antibiotic effect, which is a valuable pharmacokinetic feature. We demonstrate that VmlR ABCF of B. subtilis grants significant (33-fold increase in MIC) protection from iboxamycin, while LsaA ABCF of E. faecalis grants an 8-fold protective effect. Furthermore, the VmlR-mediated iboxamycin resistance is cooperative with that mediated by the Cfr, resulting in up to a 512-fold increase in MIC.

Conclusions: While iboxamycin is a promising new antilisterial agent, our findings suggest that emergence and spread of ABCF ARE variants capable of defeating next-generation lincosamides in the clinic is possible and should be closely monitored.