Skip to main content

An engineered prodrug selectively suppresses β-lactam resistant bacteria in a mixed microbial setting.

Publication ,  Journal Article
Duda, AM; Ma, HR; Villalobos, CA; Kuhn, SA; He, K; Seay, SR; Jackson, AC; Suh, CM; Puccio, EA; Anderson, DJ; Fowler, VG; You, L; Franz, KJ
Published in: bioRxiv
August 3, 2024

The rise of β-lactam resistance necessitates new strategies to combat bacterial infections. We purposefully engineered the β-lactam prodrug AcephPT to exploit β-lactamase activity to selectively suppress resistant bacteria producing extended-spectrum-β-lactamases (ESBLs). Selective targeting of resistant bacteria requires avoiding interaction with penicillin-binding proteins, the conventional targets of β-lactam antibiotics, while maintaining recognition by ESBLs to activate AcephPT only in resistant cells. Computational approaches provide a rationale for structural modifications to the prodrug to achieve this biased activity. We show AcephPT selectively suppresses gram-negative ESBL-producing bacteria in clonal populations and in mixed microbial cultures, with effective selectivity for both lab strains and clinical isolates expressing ESBLs. Time-course NMR experiments confirm hydrolytic activation of AcephPT exclusively by ESBL-producing bacteria. In mixed microbial cultures, AcephPT suppresses proliferation of ESBL-producing strains while sustaining growth of β-lactamase-non-producing bacteria, highlighting its potential to combat β-lactam resistance while promoting antimicrobial stewardship.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

bioRxiv

DOI

EISSN

2692-8205

Publication Date

August 3, 2024

Location

United States
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Duda, A. M., Ma, H. R., Villalobos, C. A., Kuhn, S. A., He, K., Seay, S. R., … Franz, K. J. (2024). An engineered prodrug selectively suppresses β-lactam resistant bacteria in a mixed microbial setting. BioRxiv. https://doi.org/10.1101/2024.08.02.606422
Duda, Addison M., Helena R. Ma, César A. Villalobos, Sophia A. Kuhn, Katherine He, Sarah R. Seay, Abigail C. Jackson, et al. “An engineered prodrug selectively suppresses β-lactam resistant bacteria in a mixed microbial setting.BioRxiv, August 3, 2024. https://doi.org/10.1101/2024.08.02.606422.
Duda AM, Ma HR, Villalobos CA, Kuhn SA, He K, Seay SR, et al. An engineered prodrug selectively suppresses β-lactam resistant bacteria in a mixed microbial setting. bioRxiv. 2024 Aug 3;
Duda, Addison M., et al. “An engineered prodrug selectively suppresses β-lactam resistant bacteria in a mixed microbial setting.BioRxiv, Aug. 2024. Pubmed, doi:10.1101/2024.08.02.606422.
Duda AM, Ma HR, Villalobos CA, Kuhn SA, He K, Seay SR, Jackson AC, Suh CM, Puccio EA, Anderson DJ, Fowler VG, You L, Franz KJ. An engineered prodrug selectively suppresses β-lactam resistant bacteria in a mixed microbial setting. bioRxiv. 2024 Aug 3;

Published In

bioRxiv

DOI

EISSN

2692-8205

Publication Date

August 3, 2024

Location

United States