Switching on the activity of 1,5-diaryl-pyrrole derivatives against drug-resistant ESKAPE bacteria: Structure-activity relationships and mode of action studies

• Published in: European journal of medicinal chemistry Vol. 178; pp. 500 - 514
• Main Authors: Masci, Domiziana, Hind, Charlotte, Islam, Mohammad K., Toscani, Anita, Clifford, Melanie, Coluccia, Antonio, Conforti, Irene, Touitou, Meir, Memdouh, Siham, Wei, Xumin, La Regina, Giuseppe, Silvestri, Romano, Sutton, J. Mark, Castagnolo, Daniele
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.09.2019; Elsevier
• Subjects: Antimicrobial resistance; Chemistry, Medicinal; DNA gyrase; Drug resistance; ESKAPE bacteria; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Pyrrole; Science & Technology; NCTC; EMRSA; VRE; VSE; RND; ESKAPE; PaβN; Drug resistance; PMBN; DNA gyrase; NBTI; ESKAPE bacteria; Pyrrole; Antimicrobial resistance; OUTER-MEMBRANE; DESIGN; SUSCEPTIBILITY; DISCOVERY; MOLECULES; GRAM-NEGATIVE BACTERIA; ANTIBACTERIAL ACTIVITY; ANTIMYCOBACTERIAL AGENTS; INHIBITORS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.05.087

Antibiotic resistance represents a major threat worldwide. Gram-positive and Gram-negative opportunistic pathogens are becoming resistant to all known drugs mainly because of the overuse and misuse of these medications and the lack of new antibiotic development by the pharmaceutical industry. There is an urgent need to discover structurally innovative antibacterial agents for which no pre-existing resistance is known. This work describes the identification, synthesis and biological evaluation of a novel series of 1,5-diphenylpyrrole compounds 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 pathogens at concentrations similar or lower than levofloxacin. Microbiology studies revealed that the plausible target of the pyrrole derivatives 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. [Display omitted] •Novel 1,5-diphenyl-pyrrole derivatives were synthesized.•The new compounds are endowed with high antibacterial activity.•The phenyl substituents at N1 and C5 of the pyrroles is essential for activity.•Protonatable guanidine/amino moieties improve the activity against Gram-ve bacteria.•Bacterial DNA gyrase was identified as a plausible target.