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

Brodiazhenko, Tetiana ; Turnbull, Kathryn Jane ; Wu, Kelvin J Y ; Hiraku, Takada LU ; Tresco, Ben I C ; Tenson, Tanel ; Myers, Andrew G and Hauryliuk, Vasili LU orcid (2022) In JAC - Antimicrobial Resistance 4(3). p.1-8
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... (More)

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.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
JAC - Antimicrobial Resistance
volume
4
issue
3
article number
dlac061
pages
1 - 8
publisher
Oxford University Press
external identifiers
  • pmid:35733912
  • scopus:85135910403
ISSN
2632-1823
DOI
10.1093/jacamr/dlac061
language
English
LU publication?
yes
additional info
© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.
id
3ac4228b-ff24-42f4-9373-51f4c8ece822
date added to LUP
2022-06-25 15:03:10
date last changed
2024-06-27 17:39:02
@article{3ac4228b-ff24-42f4-9373-51f4c8ece822,
  abstract     = {{<p>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.</p><p>Objectives: We have established newly developed lincosamide iboxamycin as a potential novel antilisterial agent.</p><p>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.</p><p>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.</p><p>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.</p>}},
  author       = {{Brodiazhenko, Tetiana and Turnbull, Kathryn Jane and Wu, Kelvin J Y and Hiraku, Takada and Tresco, Ben I C and Tenson, Tanel and Myers, Andrew G and Hauryliuk, Vasili}},
  issn         = {{2632-1823}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{1--8}},
  publisher    = {{Oxford University Press}},
  series       = {{JAC - Antimicrobial Resistance}},
  title        = {{Synthetic oxepanoprolinamide iboxamycin is active against Listeria monocytogenes despite the intrinsic resistance mediated by VgaL/Lmo0919 ABCF ATPase}},
  url          = {{http://dx.doi.org/10.1093/jacamr/dlac061}},
  doi          = {{10.1093/jacamr/dlac061}},
  volume       = {{4}},
  year         = {{2022}},
}