Beta-lactam enhancement against methicillin-resistant Staphylococcus aureus by cell wall blockade is autolysis-dependent: a butyrolactone derivative as case in point
- 1Creighton University
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is non-susceptible to beta-lactams. Blockade of cell wall biosynthesis is a potential target for beta-lactam enhancement but requires further investigation. A butyrolactone derivative enhanced beta-lactams against MRSA strains by reducing the availability of D-Ala-D-Ala. Unlike D-cycloserine, it did not inhibit D-Ala-D-Ala ligase (Ddl). Nor did it show an additive or synergistic effect when combined with cycloserine, indicating a unique mechanism for blocking cell wall precursor production that does not involve the traditional Lipid II pathway. Notably, beta-lactam potentiation by our chemical or D-cycloserine was highly dependent on the intrinsic autolytic ability of the tested MRSA strains. Strains that resisted lysis upon Triton X-100 exposure showed a minimal increase in beta-lactam susceptibility, whereas highly autolytic strains showed significant changes in their beta-lactam MICs. We have thus identified autolytic ability as the Achilles Heel in the strategy of targeting cell wall biosynthesis for beta-lactam potentiation.
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BibTeX
@misc{magdum2026betalactam,
title = {{Beta-lactam enhancement against methicillin-resistant Staphylococcus aureus by cell wall blockade is autolysis-dependent: a butyrolactone derivative as case in point}},
author = {P. M. Magdum and J. N. Grissom and B. T. Franey and S. Ullah and M. H. Abdelaziz and J. North and A. Sarkar},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.26.754631},
url = {https://www.biorxiv.org/content/10.64898/2026.09.26.754631v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Beta-lactam enhancement against methicillin-resistant Staphylococcus aureus by cell wall blockade is autolysis-dependent: a butyrolactone derivative as case in point
AU - P. M. Magdum
AU - J. N. Grissom
AU - B. T. Franey
AU - S. Ullah
AU - M. H. Abdelaziz
AU - J. North
AU - A. Sarkar
PY - 2026
DA - 2026/09/26
PB - bioRxiv
DO - 10.64898/2026.09.26.754631
UR - https://www.biorxiv.org/content/10.64898/2026.09.26.754631v1
AB - Methicillin-resistant Staphylococcus aureus (MRSA) is non-susceptible to beta-lactams. Blockade of cell wall biosynthesis is a potential target for beta-lactam enhancement but requires further investigation. A butyrolactone derivative enhanced beta-lactams against MRSA strains by reducing the availability of D-Ala-D-Ala. Unlike D-cycloserine, it did not inhibit D-Ala-D-Ala ligase (Ddl). Nor did it show an additive or synergistic effect when combined with cycloserine, indicating a unique mechanism for blocking cell wall precursor production that does not involve the traditional Lipid II pathway. Notably, beta-lactam potentiation by our chemical or D-cycloserine was highly dependent on the intrinsic autolytic ability of the tested MRSA strains. Strains that resisted lysis upon Triton X-100 exposure showed a minimal increase in beta-lactam susceptibility, whereas highly autolytic strains showed significant changes in their beta-lactam MICs. We have thus identified autolytic ability as the Achilles Heel in the strategy of targeting cell wall biosynthesis for beta-lactam potentiation.
ER -