Development of Peptide-based Metallo-ß-lactamase Inhibitors as a New Strategy to Combat Antimicrobial Resistance: A Mini-review.

Global dissemination of antimicrobial resistance (AMR) not only poses a significant threat to human health, food security, and social development but also results in millions of deaths each year. In Gram-negative bacteria, the primary mechanism of resistance to ß-lactam antibiotics is the production of ß-lactamases, one of which is carbapenem-hydrolyzing ß-lactamases known as carbapenemases. As a general scheme, these enzymes are divided into Ambler class A, B, C, and D based on their protein sequence homology. Class B ß-lactamases are also known as metallo-ß-lactamases (MBLs). The incidence of recovery of bacteria expressing metallo-ß- lactamases (MBLs) has increased dramatically in recent years, almost reaching a pandemic proportion. MBLs can be further divided into three subclasses (B1, B2, and B3) based on the homology of protein sequences as well as the differences in zinc coordination. The development of inhibitors is one effective strategy to suppress the activities of MBLs and restore the activity of ß-lactam antibiotics. Although thousands of MBL inhibitors have been reported, none have been approved for clinical use. This review describes the clinical application potential of peptide-based drugs that exhibit inhibitory activity against MBLs identified in past decades. In this report, peptide-based inhibitors of MBLs are divided into several groups based on the mode of action, highlighting compounds of promising properties that are suitable for further advancement. We discuss how traditional computational tools, such as in silico screening and molecular docking, along with new methods, such as deep learning and machine learning, enable a more accurate and efficient design of peptide-based inhibitors of MBLs.

Bactericidal, anti-biofilm, and anti-virulence activity of vitamin C against carbapenem-resistant hypervirulent Klebsiella pneumoniae.

The emergence of carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) causing high mortality in clinical patients infers the urgent need for developing therapeutic agents. Here, we demonstrated vitamin C (VC) exhibited strong bactericidal, anti-biofilm, and virulence-suppressing effects on CR-hvKP. Our results showed such a bactericidal effect is dose-dependent both in vitro and in the mouse infection model and is associated with induction of reactive oxygen species (ROS) generation. In addition, VC inhibited biofilm formation of CR-hvKP through suppressing the production of exopolysaccharide (EPS). In addition, VC acted as an efflux pump inhibitor at subminimum inhibitory concentration (sub-MIC) to disrupt transportation of EPS and capsular polysaccharide to bacterial cell surface, thereby further inhibiting biofilm and capsule formation. Furthermore, virulence-associated genes in CR-hvKP exposed to sub-MIC of VC were downregulated. Our findings indicated VC could be an effective and safe therapeutic agent to treat CR-hvKP infections in urgent cases when all current treatment options fail.