Design, synthesis and characterization of peptidyl boronate analogues as effective antimicrobial agents

Abstract

Antibiotic-resistant penicillin binding protein (PBPs) production is one of the reasons why bacteria develop resistance to β-lactam antibiotics, and this needs to be tackled in the continual battle to produce effective antibiotics. The transition state analogue of boronic acid inhibitors mimicking the structures and interactions of good penicillin substrates are known to be potent β-lactamase inhibitors. We have recently identified boronic acids as a selective scaffold for Actinomadura sp. strain R39 DD-peptidase (PBP). Here, we report the synthesis and biological evaluation of a comprehensive set of 16 boronic acid analogues and establish their structure–activity relationships as well as their potential for use as PBP inhibitors. The docking studies of all the synthesized compounds were carried out in Molegro Virtual Docker. Of the 16 compounds synthesized, compound 8e exhibits the highest binding affinity (187.5 kcal/mol) followed by compounds 8f, 8d, 8a, 8g, 8c and 8i. The minimum inhibitory concentration (MIC) of all the 16 synthesised compounds 6a–6f, 8a–8i, 10 and 11 were tested against two Gram-positive (S. aureus, and S. pyogene) and eight Gram-negative (E. coli, C. koseri, K. oxytoca, K. pneumoniae, S. dysentriae, S. typhi, C. fruendi, and P. aeruginosa) bacteria. The biological evaluation of the synthesized boronic acid analogues were found to be effective in all cases, although it is more pronounced for pyrazine-containing dipeptidyl boronic acid (8e, MIC = 0.062 mg/ml) and hence considered as an effective inhibitor, thereby highlighting the importance of phenylalanine as linker and heterocyclic aromatic carboxylic acid as terminal moieties. This study exemplifies that pyrazine-containing dipeptidyl boronic acid (8e) as a PBP inhibitor could open up new avenues in the development of PBP-inhibiting molecules that eventually display bactericidal effects on distinct bacterial species.