An Original and Efficient Antibiotic Adjuvant Strategy to Enhance the Activity of Macrolide Antibiotics against Gram-Negative Resistant Strains

Abstract

Gram-negative bacteria were reported as a significant cause of infections in both community and nosocomial settings. Considered as one of the greatest threats to public health, the spread of bacteria drug resistance and the lack of effective alternative treatment options remains problematic. Herein, we report a promising strategy to combat Gram-negative resistant strains consisting of the combination of a macrolide antibiotic with a polyaminoisoprenyl adjuvant derivative leading to a significant decrease of antibiotic resistance.

Keywords: Gram-negative bacterial strains; antibiotic adjuvants; macrolide antibiotics; outer membrane; polyamines; polyaminoisoprenyl derivatives.

Figure 1

Structure of the macrolides used in this study and their associated LogKow values.

Figure 2

Correlation of the gain factor observed toward numerous Gram-negative bacteria depending on the LogKow value of the considered macrolide antibiotic.

Figure 3

Inner membrane depolarization of various Gram-negative bacteria (PA01, E. coli ATCC 25922, K. pneumoniae ATCC 13883, C. koseri IP8294, E. cloacae DSM 129, K. aerogenes ATCC 13048, K. aerogenes 289 (MDR), and E. coli AG100A_pUC18) by evaluating DiSC₃(5) fluorescence recorded after 5 minutes in the presence of compound 3 at 15 µM and 125 µM. * Refers to E. coli AG100A_pUC18. The results represent the average plus SD of three independent experiments.

Figure 4

ATP release levels measurement in the presence of compound 3. ATP release levels of various Gram-negative bacteria (PA01, E. coli ATCC 25922, K. pneumoniae ATCC 13883, C. koseri IP8294, E. cloacae DSM 129, K. aerogenes ATCC 13048, K. aerogenes 289 (MDR), and E. coli AG100A_pUC18) evaluated after 1 minute by bioluminescence in the presence of compound 3 at 15 µM and 125 µM. In each case, polymyxin B (250 µM) was used as a positive control to quantify the maximum level of ATP efflux. * Refers to E. coli AG100A_pUC18.

Figure 5

Outer membrane permeabilization of chosen Gram-negative bacterial strains by evaluating the rate of nitrocefin hydrolysis in the presence of PPB (Potassium Phosphate Buffer), PMB, PMBn, and compound 3 at 125 µM.