Enterococci are the third to second most common pathogens in nosocomial infections. With their intrinsic resistance against cephalosporines and most other β-lactam antibiotics, the treatment of enterococcal infections remains challenging. With the rising resistance against last-resort antibiotics and the emergence of vancomycin-resistant enterococci (VRE), current therapy options are critically limited [1]. A promising way to overcome this burden is to re-sensitize resistant strains to modified approved antibiotics [2]. Therefore, we conjugated polycationic peptides to select β-lactam antibiotics using a bifunctional linker moiety. These conjugates were screened for their antimicrobial efficacy, pharmacokinetics and affinity to penicillin-binding proteins (PBPs). For the most promising ceftazidime-R6 conjugate, a broadened spectrum and up to 1000-fold-higher efficacy could be demonstrated against vancomycin-susceptible enterococci and VRE without increasing cytotoxicity. In vivo studies in rodents showed an altered way of excretion and demonstrated therapeutic efficacy against VRE. The altered PBP-binding profile as well as the faster killing mechanism of the conjugates compared to their parent β-lactam suggest an altered mode of action [3]. These findings go along with our previously reported findings on FU002, a vancomycin derivative, and represent a possible platform technology for cell-wall addressing antibiotics and particular against enterococci [4].

References:

1. Kahn A. et al. (2022), Antimicrobial Susceptibility Testing for Enterococci. J. Clin Microbil., 60(9).

2. Narendrakumar L. et al. (2023), β-Lactam potentiators to re-sensitize resistant pathogens: Discovery, development, clinical use and the way forward. Front. Microbiol., 13.

3. Werner J. et al. (2024), Conjugation of Polycationic Peptides Extends the Efficacy Spectrum of β-Lactam Antibiotics. Adv. Sci. (Weinh), e2411406.

4. Umstätter F. et al. (2020), Vancomycin Resistance Is Overcome by Conjuagtion of Poylcationic Peptides. Angew Chem Int Ed Engl., 59(23).