The growing number of multidrug resistant strains in Tunisia has become a serious health concern contributing to high rate of mortality and morbidity. Since current antibiotics are rapidly becoming ineffective, novel strategies to combat resistance are needed. Recently, we demonstrated that combination of a tetracycline antibiotic with various polyaminoisoprenyl adjuvants can sustain the life span and enhance the activity of these drugs against Pseudomonas aeruginosa reference strain (PA01). In the context of our continuing studies, the effective approach of antibiotic-adjuvant was investigated against a large panel of P. aeruginosa Tunisian clinical strains collected from the Military Hospital of Tunis. In this paper, we demonstrated that the combination of a farnesyl spermine compound 3 used at concentrations ranging from 2.5 to 10 µM, in the presence of doxycycline or minocycline leads to a significant decrease of P. aeruginosa antibiotic resistance.

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.

Antibiotics have been the cornerstone of modern medicine saving lives by virtue of being able to cure infectious diseases and to prevent infections in those who are immune compromised. Their intense use has led to a surging increase in the incidence of antibiotic-resistant bacteria resulting in a desperate need for antibiotics with new mechanisms of action. As part of our search for new antimicrobials we have screened an in-house library of compounds and identified two 3-substituted-1H-imidazol-5-yl-1H-indoles as weak growth inhibitors (MIC 16 µg/mL) against methicillin-resistant Staphylococcus aureus (MRSA). An extensive library of analogues was prepared using the Van Leusen three-component reaction, biological evaluation of which led to the identification of two analogues (26 and 32) with favorable anti-MRSA activity (MIC ≤ 0.25 µg/mL) which also lacked cytotoxic or hemolytic properties. The screening campaign also identified two derivatives, a phenethyl-indole-imidazole 57 and a 5-phenyl-1H-imidazole 111 that were non-toxic selective antifungals towards Cryptococcus neoformans. These results have identified 3-substituted-1H-imidazol-5-yl-1H-indoles and 5-phenyl-1H-imidazoles as new structural scaffolds for further investigation as anti-MRSA and anti-C. neoformans agents, respectively.