A new bactericidal chlorinated derivative containing 2-aminooxazole potentiates antibacterial action of colistin against multidrug-resistant acinetobacter baumannii

Abstract

This comprehensive study provides insight into the antibacterial action of a recently published 2-chloro-N-(oxazol-2-yl)isonicotinamide (AB15), intending to assess its potential as a candidate adjuvant molecule to support existing antibacterial drugs. Within the determination of the antibacterial effect, a promising activity against a member of the ESKAPE group with reduced treatment options, biofilm producer, Acinetobacter baumannii, was recognized (MIC of AB15 ranged from 15.63 to 62.5 mu M). In addition, AB15 exhibited bactericidal activity and non/low-toxicity in vitro (IC50 > 1000 mu M using HK-2 cells) and in vivo (LD50 > 500 mg/kg of body weight of the Galleria mellonella larvae, for both intra-hemocoel and per oral administration routes). Checkerboard assay revealed additive and synergistic interactions of AB15 and last-resort antibiotic drug, colistin (CST). Moreover, attention was also given to a frequently overlooked antibiofilm activity - the ability to suppress bacterial dissemination from microbial biofilms, and parameter MBDC (minimum biofilm dissemination concentration) was introduced. The study of the antibiofilm activity of AB15 and CST, both acting individually, or in AB15 + CST combination, revealed that AB15 has significant potential to suppress bacterial dissemination from biofilm formed by a clinical isolate Acinetobacter baumannii and that it contributes to this effect when combined with CST. Finally, AB15 + CST combination demonstrated significantly greater biocompatibility towards human erythrocytes than CST acting individually at an equivalent antibiofilm-effective concentration. The role of AB15 as a promising adjuvant molecule to CST is also supported by its distinct mechanism of action, which reduces the risk of antimicrobial resistance emergence. To conclude, AB15 exhibits several essential attributes that support its designation as a promising antibiotic adjuvant.