SF- and SCF-substituted tetrahydroquinoline compounds as potent bactericidal agents against multidrug-resistant persister Gram-positive bacteria.

Bacteria persister cells are immune to most antibiotics and hence compounds that are active against persister bacteria are needed. We screened a chemical library of SF- and SCF-substituted tetrahydroquinoline compounds, synthesized the Povarov reaction, for antibacterial activity and identified active compounds that displayed good activities against many Gram-positive bacteria, including persisters. The most potent of these compounds, , inhibited the growth of drug-resistant Gram-positive bacterial pathogens (including clinical strains) at concentrations ranging from 1 μg mL to 4 μg mL. Several of the SCF- and SF-containing compounds were active against methicillin-resistant (MRSA) and against the two most fatal strains of vancomycin-resistant (VRE), VRE and VRE . The compounds showed bactericidal activity against stationary phase persister MRSA in time-kill assays. Mechanistic studies showed that acts by disrupting bacterial membranes. Scanning electron microscopy (SEM) was used to confirm bacterial membrane disruption. Interestingly, in a 30 day serial exposure experiment, MRSA remained susceptible to low-dose whilst resistance to ciprofloxacin and mupirocin emerged by day 10. Analogs of , which did not bear the SF or SCF moieties, were inactive against bacteria. Recent reports (G. A. Naclerio, N. S. Abutaleb, K. I. Onyedibe, M. N. Seleem and H. O. Sintim, 2020, , 102-110 and G. A. Naclerio, N. S. Abutaleb, D. Li, M. N. Seleem and H. O. Sintim, 2020, (20), 11934-11944) also demonstrated that adding the SF or SCF groups to a different scaffold (oxadiazoles) enhanced the antibacterial properties of the compounds, so it appears that these groups are privileged moieties that enhance the antimicrobial activities of compounds.