Antimicrobial Peptides from Human Microbiome Against Multidrug Efflux Pump of Pseudomonas aeruginosa: a Computational Study.

Abstract

The excess use of antibiotics has led to the evolution of multidrug-resistant pathogenic strains causing worldwide havoc. These multidrug-resistant strains require potent inhibitors. Pseudomonas aeruginosa is a lead cause of nosocomial infections and also feature in the critical priority list of the world health organization (WHO) for the development of new antibiotics against their antimicrobial resistance. Antimicrobial peptides (AMPs) found in almost every life form from microorganisms to humans are known to defend their hosts against various pathogens. Owing to the diversity of the human microbiome, in this study, we have identified the cell-penetrating AMPs from the human microbiome and studied their inhibitory activity against the outer membrane protein OprM of the MexAB-OprM, a constitutively expressed multidrug efflux pump of the Ps. aeruginosa. Screening of the AMPs from the human microbiome resulted in the identification of 147 cell-penetrating AMPs (CPAMPs). The virtual screening of these CPAMPs against the OprM protein showed significant inhibitory results with the top docked AMP showing binding affinity exceeding -30 kcal/mol. The molecular dynamic simulation determined the interaction stabilities between the AMPs and the OprM at the binding site. Further, the residue interaction networks (RINs) are analyses to identify the inhibitory patterns. Later, these patterns were confirmed by MM-PBSA analysis suggesting that the AMPs are majorly stabilized by electrostatic interactions at the binding site. Thus, the high binding affinity and insights from the molecular interaction signify that the identified CPAMPs from the human microbiome can be further explored as inhibitory agents against multidrug-resistant Ps. aeruginosa.