SF5 and SCF3-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 SF5 and SCF3-substituted tetrahydroquinoline compounds, synthesized via 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, HSD1835, inhibited 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 SCF3 and SF5 containing compounds were active against methicillin-resistant Staphylococcus aureus (MRSA) and against the two most fatal strains of vancomycin-resistant Enterococcus (VRE), VRE faecalis and VRE faecium. The compounds showed bactericidal activity against stationary phase persister MRSA in time kill assays. Mechanistic studies showed that HSD1835 act by permeabilizing 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 HSD1835 whilst resistance to ciprofloxacin and mupirocin emerged by day 10. Analogs of HSD1835, which did not bear the SF5 or SCF3 moieties, were inactive against bacteria. Recent reports, RSC Med. Chem. 2020, 11, 102-110 and J. Med. Chem. 2020, 63, 20, 11934-11944, also demonstrated that adding the SF5 or SCF3 groups to a different scaffold (oxadiazoles) enhanced antibacterial properties of the compounds so it appears that these groups are privileged moieties that enhance the antimicrobial activities of compounds.