Switching on the activity of 1,5-diaryl-pyrrole derivatives against drug-resistant ESKAPE bacteria

Antibiotic resistance represents a significant threat worldwide. There is an urgent need to discover structurally innovative antibacterial agents for which no pre-existing resistance is known. With the aim to speed up the drug discovery process and to reduce the limitations of target-based high-through put screenings (HTS) we envisioned N-((1-(4-chlorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methyl)cyclohexanamine (pyrrole 1) through an alternative strategy based on the molecular hybridization of known drugs. Pyrrole 1 is a promising novel agent as it shows potent activity against various mycobacteria, including multi drug resistant (MDR) tuberculosis strains. A subsequent structure-activity relationship (SAR) study revealed that the introduction of a phenyl ring on C5 of the pyrrole was a key element to switch the selectivity and the antimicrobial activity from mycobacteria to Gram+ve bacteria. Based on these results, we designed and synthesized a new series of 1,5-diaryl-pyrrole derivatives active against a panel of ESKAPE bacteria. The new compounds show high activity against both wild type and drug-resistant Gram+ve and Gram-ve bacteria at concentrations similar than levofloxacin. Microbiology studies revealed that the plausible target of this class of compounds is the bacterial DNA gyrase, with the pyrrole derivatives displaying similar inhibitory activity to levofloxacin against the wild type enzyme and retaining activity against the fluoroquinolone-resistant enzyme.