In-vitro and in-vivo efficacy of LpxC inhibitor, CHIR-090, alone or combined with colistin against Pseudomonas aeruginosa biofilm. [PublishAheadOfPrint]

With the rapid spread of antimicrobial resistance in Gram-negative pathogens, biofilms-associated infections are increasingly harder to treat and combination therapy with colistin has become one of the most efficient therapeutic strategies. Our study aimed to evaluate the potential for synergy of colistin combined with CHIR-090, a potent LpxC inhibitor, against in-vitro and in-vivo Pseudomonas aeruginosa biofilms. Four P. aeruginosa isolates with varying colistin susceptibility were chosen for evaluation. Tested isolates of P. aeruginosa exhibited MIC values ranging from 1 to 64 and 0.0625 to 0.5 μg/ml for colistin and CHIR-090, respectively. Against 24h static biofilms, MBEC values ranged from 256 to 512 and 8 to >128 μg/ml for colistin and CHIR-090, respectively. Interestingly, sub-inhibitory concentrations of CHIR-090 contributed to eradicate subpopulations of P. aeruginosa with highest colistin MIC values. Combination of colistin and CHIR-090 at sub-inhibitory concentrations demonstrated synergistic activity, both in-vivo and in-vitro, and prevented the formation of colistin tolerant sub-populations in in-vitro biofilms. In summary, our study highlights the in-vivo and in-vitro synergistic activity of colistin and CHIR-090 combination against both colistin-susceptible and non-susceptible P. aeruginosa biofilms. Further studies are warranted to investigate the clinical relevance of the combination of these two antimicrobials and outline the underlying mechanism for their synergistic action.

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