Neisseria gonorrhoeae Ketol-Acid Reductoisomerase Is a Potential Therapeutic Target

Abstract

The host-adapted human pathogen Neisseria gonorrhoeae is the causative agent of sexually transmitted infection gonorrhea. The increased emergence of gonorrhea infections worldwide, associated with the surging resistance to antimicrobial treatments is alarming. Antimicrobial resistance (AMR) is a global threat to human health and occur through various molecular mechanisms. This research aims to identify molecular therapeutic targets in N. gonorhoeae as a potential antibiotic adjuvant. This work is focused on ketol acid reductor-isomerase enzyme (KARI), an enzyme involved in the branched-chain amino acids biosynthesis. A BLASTp analysis revealed that KARI enzyme is highly conserved in N. gonorrhoeae strains and present in important bacterial pathogens including ESKAPE. Sequence alignment of different KARI proteins from various human bacterial pathogens and gut microbiota demonstrate that residues forming the active site and cofactors binding sites are conserved among all tested KARIs. A 3D homology-based model for gonococcal KARI was generated using Swiss model server and the KARI template from S. aureus. The generated 3D KARI model shows that this enzyme adapts a different conformation upon binding of cofactors, allowing the substrate binding and catalysis, while the active site adapts a closed state.