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
(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.
(Less)
- author
- 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
- organization
- publishing date
- 2022-06
- 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
-
- scopus:85135910403
- pmid:35733912
- 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
- 2025-05-02 22:32:20
@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}},
}