Abstract:
The Antimicrobial Resistance (AMR) is a leading cause of death worldwide;
therefore, AMR is a global health concern. The growing AMR has made it difficult to
treat carbapenem-resistant Acinetobacter baumannii (CRAB) infections with available
therapeutics, such as antibiotics. World Health Organization (WHO) has declared
CRAB a critical priority pathogen against which there is an urgent need to develop new
antibiotics or look for an alternative therapeutic treatment. Antimicrobial peptides
(AMPs) are part of the innate immune system and have remarkably diverse structures
and functions. AMPs can kill infectious agents (such as bacteria, viruses, and fungi)
either directly or indirectly through the modulation of immune processes. Natural
AMPs are less immunogenic and have the potential to become cytotoxic, limiting their
clinical application. Di-sulfide engineering of AMPs has been proven to not only
enhance their antimicrobial activity but also their stability. Therefore, in this study, we
created a library of 144 AMPs, consisting of both natural AMPs and their mutants, via
disulfide engineering. Following physicochemical property assessment, 17 prioritized
AMPs were individually docked with each of the six main carbapenemases present in
CRAB. Among the three strong AMP mutants, 7M4,17M2 and 17M4, the mutant 7M4
had consistently high affinity for GES11, KPC2, NDM1, OXA23, OXA58, and VIM1.
Moreover, residue-level stable topologies of high-affinity peptide-protein complexes
were explained by coarse-grained clustering and flexibility analysis. 7M4 had the
highest affinity for NDM1 due to its ability to form hydrogen bonds and hydrophobic
interactions with the metallo-β-lactamase domain of the target protein. The stability of
the 7M4-NDM1 complex was confirmed by molecular dynamics (MD) simulations.
This study provides experimental validation and a similar methodology for designing
potential therapeutic AMPs against other drug-resistant pathogens.
