Subtractive proteomic analysis for identification of potential drug targets and vaccine candidates against Burkholderia pseudomallei K96243

Abstract

Burkholderia pseudomallei is regarded as a global threat because of its ability to cause melioidosis, and potential as bioweapon. Intrinsic resistance to frontline antibiotics remains a major challenge in treating melioidosis. The increasing global burden of B. pseudomallei triggers the need to develop effective drugs and vaccine for controlling this pathogen. Therefore, we analyzed the whole proteome of B. pseudomallei K96243 using subtractive proteomic and immune-informatic analysis to find out potential drug target and vaccine candidate. Our analysis revealed 45 essential and non-homologous metabolic proteins, involved in different unique metabolic pathways. 36 out of 45 proteins can serve as novel drug targets and the remaining proteins had already been targeted with experimental drugs. 2 novel targets of cytoplasmic localization, namely dihydroneopterin aldolase and phosphoribosyl transferase were subjected to molecular docking with 14 antibiotics, which revealed the strong binding affinity of cefiderocol and tetracycline to the identified targets. Moreover, 100 ns molecular dynamic simulation and MM-PBSA calculation revealed the stability of drug-protein complexes. On the contrary, highly antigenic, non-allergic and non-toxic epitopes from three essential outer membrane proteins were joined by linkers and adjuvant to construct a chimeric peptide vaccine. The vaccine construct could efficiently bind to TLR-4 and generated robust immune response. The vaccine-receptor complex showed minimum deformability and good stability. Overall, our findings will aid in designing new inhibitors that disrupts the functionality of proposed targets and in the development of subunit vaccine for the therapeutic and prophylactic management of B. pseudomallei.