Optimization of Pyrazole Compounds as Antibiotic Adjuvants Active against Colistin- and Carbapenem-Resistant Acinetobacter baumannii

Abstract

The diffusion of antibiotic-resistant, Gram-negative, opportunistic pathogens, an increasingly important global public health issue, causes a significant socioeconomic burden. Acinetobacter baumannii isolates, despite causing a lower number of infections than Enterobacterales, often show multidrug-resistant phenotypes. Carbapenem resistance is also rather common, prompting the WHO to include carbapenem-resistant A. baumannii as a “critical priority” for the discovery and development of new antibacterial agents. In a previous work, we identified several series of compounds showing either direct-acting or synergistic activity against relevant Gram-negative species, including A. baumannii. Among these, two pyrazole compounds, despite being devoid of any direct-acting activity, showed remarkable synergistic activity in the presence of a subinhibitory concentration of colistin on K. pneumoniae and A. baumannii and served as a starting point for the synthesis of new analogues. In this work, a new series of 47 pyrazole compounds was synthesized. Some compounds showed significant direct-acting antibacterial activity on Gram-positive organisms. Furthermore, an evaluation of their activity as potential antibiotic adjuvants allowed for the identification of two highly active compounds on MDR Acinetobacter baumannii, including colistin-resistant isolates. This work confirms the interest in pyrazole amides as a starting point for the optimization of synergistic antibacterial compounds active on antibiotic-resistant, Gram-negative pathogens.

4-Trifluoromethyl bithiazoles as broad-spectrum antimicrobial agents for virus-related bacterial infections or co-infections

“…The minimum antibacterial concentration (MAC) of the compounds was determined in the presence of a fixed and subinhibitory (corresponding to 0.5 × MIC) concentration of colistin (0.12 μg mL −1 for E. coli CCUGT and K. pneumoniae ATCC 13833; 0.25 μg mL −1 for A. baumannii ATCC 17978 and P. aeruginosa ATCC 27853). 48 Selected compounds were also tested on clinical isolates with well-characterized resistance phenotypes (Table 2) that were present in our collection and were described elsewhere. 49 Similarly, both the MIC and MAC values were determined with colistin-resistant Gram-negative isolates (colistin MIC values for E. coli SI-63, K. pneumoniae BO04, A. baumannii N50 and P. aeruginosa SI-270; 4, 256, 16 and 128 μg mL −1 , respectively), but using a fixed concentration of colistin equal to 2 μg mL −1 , i.e.…”

PYED-1 Overcomes Colistin Resistance in Acinetobacter baumannii

“…In the presence of PYED-1, the MBC/MIC ratio of colistin was less than or equal to 4 for all strains, indicating that the combination colistin/PYED-1 favors killing of A. baumannii at concentrations that are ineffective as monotherapy. In recent years, several colistin adjuvant molecules, both antibiotic and non-antibiotic, have been identified to treat infections caused by extensively drug-resistant A. baumannii [35][36][37][38]. Some synergic combinations have been approved by the Food and Drug Administration (FDA) [39,40].…”