In Vitro and In Vivo Efficacy of an LpxC Inhibitor, CHIR-090, Alone or Combined with Colistin against Pseudomonas aeruginosa Biofilm

Abstract

With the rapid spread of antimicrobial resistance in Gram-negative pathogens, biofilm-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 the 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 various colistin susceptibilities were chosen for evaluation. The tested isolates of P. aeruginosa exhibited MIC values ranging from 1 to 64 and 0.0625 to 0.5 g/ml for colistin and CHIR-090, respectively. Against 24-h static biofilms, minimum biofilm eradication concentration values ranged from 256 to 512 and 8 to Ͼ128 g/ml for colistin and CHIR-090, respectively. Interestingly, subinhibitory concentrations of CHIR-090 contributed to the eradication of subpopulations of P. aeruginosa with the highest colistin MIC values. The combination of colistin and CHIR-090 at subinhibitory concentrations demonstrated synergistic activity both in vivo and in vitro and prevented the formation of colistin-tolerant subpopulations in in vitro biofilms. In summary, our study highlights the in vivo and in vitro synergistic activity of the colistin and CHIR-090 combination against both colistin-susceptible and -nonsusceptible 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.

Towards the sustainable discovery and development of new antibiotics

“…Further opportunities remain to improve the discovery and development of agents for combination therapy as indicated above, i.e. compounds that act synergistically against multidrug-resistant and/or high-priority pathogens 193 , 194 . The discrimination of specific synergistic activities from non-specific antibiotic activities remains a challenge during the discovery process.…”

Chemical Highlights Supporting the Role of Lipid A in Efficient Biological Adaptation of Gram-Negative Bacteria to External Stresses

“…107,146,[147][148] This was the first LpxC inhibitor capable of inhibiting the growth of P. aeruginosa with an IC 50 < 2.1 nM. 137 Interestingly, Tan et al evaluated the activity of colistin in combination with 19 against P. aeruginosa biofilms and observed synergistic activities at subinhibitory concentrations in vitro and in vivo 149 , using a checkerboard assay and biofilm conditions, synergy (FIC 0.34) was reported not only against colistin-susceptible P. aeruginosa biofilms but also resistant strains. 149 To determine the role of efflux in modulating the susceptibility of P. aeruginosa to 19, Caughlan et al compared wildtype PA01 with mutants lacking MexAB-OprM or MexXY-OprM efflux pumps and demonstrated that the deletion of mexB contributed to a 4-fold increase in susceptibility, suggesting that compound 19 is a substrate of the MexB pump.…”

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“…Their blockage helped control the spread of the pathogens and decrease their pathogenicity. Besides, their combinational use with antibiotics made the cell wall weaker for the entrance of antibiotics into the host cells[37][38][39][40]. The second part, core oligosaccharide, is composed of a short chain of sugars such as KDO and heptose.…”