Crystal structure of calcium bound outer membrane phospholipase A (OmpLA) fromSalmonella typhiandin silicoanti-microbial screening

Abstract

AbstractAntimicrobial resistance is widespread inSalmonellainfections that affect millions worldwide.Salmonella typhiand other Gram-negative bacterial pathogens encode an outer membrane phospholipase A (OmpLA), crucial for their membrane integrity. Further, OmpLA is implicated in pathogen internalization, haemolysis, acid tolerance, virulence and sustained infection in human hosts. OmpLA is an attractive drug target for developing novel anti-microbials that attenuate virulence, as the abrogation of OmpLA encodingpldAgene causes loss of virulence. Here, we present the crystal structure ofSalmonella typhiOmpLA in dimeric calcium bound activated state at 2.95 Å. Structure analysis suggests that OmpLA is a potential druggable target. Further, we have identified and shortlisted small molecules that bind at the dimer interface using structure basedin silicoscreening, docking and molecular dynamics. While it requires further experimental validation, anti-microbial discovery targeting OmpLA from gram-negative pathogens offers an advantage as OmpLA is required for virulence.