THCz: Small molecules with antimicrobial activity that block cell wall lipid intermediates

Abstract

Emerging antibiotic resistance demands identification of novel antibacterial compound classes. A bacterial whole-cell screen based on pneumococcal autolysin-mediated lysis induction was developed to identify potential bacterial cell wall synthesis inhibitors. A hit class comprising a 1-amino substituted tetrahydrocarbazole (THCz) scaffold, containing two essential amine groups, displayed bactericidal activity against a broad range of gram-positive and selected gram-negative pathogens in the low micromolar range. Mode of action studies revealed that THCz inhibit cell envelope synthesis by targeting undecaprenyl pyrophosphate–containing lipid intermediates and thus simultaneously inhibit peptidoglycan, teichoic acid, and polysaccharide capsule biosynthesis. Resistance did not readily develop in vitro, and the ease of synthesizing and modifying these small molecules, as compared to natural lipid II–binding antibiotics, makes THCz promising scaffolds for development of cell wall–targeting antimicrobials.

Discrete Molecular Aggregates Based on ZnII and SbIII/V Ions Displaying Efficient Antibacterial and Antioxidant Properties

“…Along with the natural sources, the chemical synthesis of compounds opens the scope for new antibacterial drug discovery . Arylfluorosulfates, THCZ, and synthetic flavonoids are commonly used drugs to treat multidrug-resistant bacteria . The antibacterial activity of synthesized compounds was examined using the broth microdilution method against six bacterial reference pathogen strains.…”

Investigation into the Mechanism of Action of the Tuberculosis Drug Candidate SQ109 and Its Metabolites and Analogues in Mycobacteria

“…However, the topical antibacterial drug bacitracin inhibits UppP activity in an indirect manner by binding to the Upp substrate . The inhibitor THCz-1 is also proposed to function in a similar manner by binding to the diphosphate moiety in, for example, Upp, Lipid I, and Lipid II …”

“…A third possibility is that the inhibitors do not actually bind to the active site, and instead, they bind to a substrate diphosphate group. This latter mechanism has been shown to occur with another bacterial cell growth inhibitor, THCz-1, which has been proposed to bind to diphosphate groups in Upp, lipids I, II, and III by means of an electrostatic interaction with the diamine fragmentas also present in SQ109. We found that THCz-1 has activity (IC 50 = 14 ± 0.03 μM) against M.…”

“…26 The inhibitor THCz-1 is also proposed to function in a similar manner by binding to the diphosphate moiety in, for example, Upp, Lipid I, and Lipid II. 27 In earlier work, we found that EcUppP activity was inhibited by the aminoguanidine 25, Figure 3a, with an IC 50 = 6 μM, 28 and 25 has at least modest structural similarity to SQ109 in that it has a very basic headgroup and a very hydrophobic "tail". We found that 25 had activity (IC 50 = ∼2 μg/mL) against Enterococcus faecalis and Enterococcus faecium, and it had uncoupling activity in an E. coli IMV assay.…”