Crystal structure of calcium bound outer membrane phospholipase A (OmpLA) from Salmonella typhi and in silico anti-microbial screening

Abstract

Antimicrobial resistance is widespread in Salmonella infections that affect millions worldwide. Salmonella typhi and 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 encoding pldA gene causes loss of virulence. Here, we present the crystal structure of Salmonella typhi OmpLA in dimeric calcium bound activated state at 2.95 [A]. 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 based in silico screening, 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.