Synthetic oxepanoprolinamide iboxamycin is highly active against human pathogen Listeria monocytogenes

Listeriosis is a dangerous food-borne bacterial disease caused by the Gram-positive Bacillota (Firmicute) bacterium Listeria monocytogenes. In this report, we show that the synthetic lincosamide iboxamycin is highly active against L. monocytogenes and can overcome the intrinsic lincosamide resistance mediated by VgaL/Lmo0919, a member of ABCF ATPase resistance determinants that act by directly removing the antibiotic from the ribosome. While iboxamycin is not bactericidal against L. monocytogenes, it displays a pronounced postantibiotic effect, which is a valuable pharmacokinetic feature. Experiments in L. monocytogenes infection models are necessary to further assess the potential of iboxamycin as a novel drug for treatment of listeriosis. We demonstrate that VmlR ARE ABCF of Bacillota bacterium Bacillus subtilis grants significant (33-fold increase in MIC) protection from iboxamycin, while LsaA ABCF of Enterococcus faecalis grants an 8-fold protective effect. Furthermore, the VmlR-mediated iboxamycin resistance is cooperative with that mediated by the Cfr 23S rRNA methyltransferase resistance determinant, resulting in up to a 512-fold increase in MIC. Therefore, emergence and spread of ABCF ARE variants capable of defeating next-generation lincosamides in the clinic is possible and should be closely monitored. ### Competing Interest Statement Andrew G. Myers is an inventor in a provisional patent application submitted by the President and Fellows of Harvard College covering oxepanoprolinamide antibiotics described in this work. Andrew G. Myers has filed the following international patent applications: WO/2019/032936 Lincosamide Antibiotics and Uses Thereof and WO/2019/032956 Lincosamide Antibiotics and Uses Thereof.