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Synthetic oxepanopr...
Synthetic oxepanoprolinamide iboxamycin is active against Listeria monocytogenes despite the intrinsic resistance mediated by VgaL/Lmo0919 ABCF ATPase
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- Brodiazhenko, Tetiana (author)
- University of Tartu
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- Turnbull, Kathryn Jane (author)
- Copenhagen University Hospital
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- Wu, Kelvin J Y (author)
- Harvard University
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- Hiraku, Takada (author)
- Lund University,Lunds universitet,Molekylär enzymologi,Forskargrupper vid Lunds universitet,Molecular Enzymology,Lund University Research Groups,Kyoto Sangyo University
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- Tresco, Ben I C (author)
- Harvard University
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- Tenson, Tanel (author)
- University of Tartu
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- Myers, Andrew G (author)
- Harvard University
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- Hauryliuk, Vasili (author)
- Lund University,Lunds universitet,Molekylär enzymologi,Forskargrupper vid Lunds universitet,Molecular Enzymology,Lund University Research Groups,University of Tartu
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(creator_code:org_t)
- 2022-06-17
- 2022
- English.
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In: JAC - Antimicrobial Resistance. - : Oxford University Press (OUP). - 2632-1823. ; 4:3, s. 1-8
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http://dx.doi.org/10... (free)
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Mikrobiologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Microbiology in the medical area (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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