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

Background: Listeriosis is a food-borne disease caused by the Gram-positive Bacillota (Firmicute) bacterium . Clinical 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 , and 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 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 and can overcome the intrinsic lincosamide resistance mediated by VgaL/Lmo0919 ABCF ATPase. While iboxamycin is not bactericidal against , it displays a pronounced post-antibiotic effect, which is a valuable pharmacokinetic feature. We demonstrate that VmlR ABCF of grants significant (33-fold increase in MIC) protection from iboxamycin, while LsaA ABCF of 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.