Clostridioides
difficile is the
leading cause of healthcare-associated infection in the U.S. and considered
an urgent threat by the Centers for Disease Control and Prevention
(CDC). Only two antibiotics, vancomycin and fidaxomicin, are FDA-approved
for the treatment of C. difficile infection
(CDI), but these therapies still suffer from high treatment failure
and recurrence. Therefore, new chemical entities to treat CDI are
needed. Trifluoromethylthio-containing N-(1,3,4-oxadiazol-2-yl)benzamides
displayed very potent activities [sub-μg/mL minimum inhibitory
concentration (MIC) values] against Gram-positive bacteria. Here,
we report remarkable antibacterial activity enhancement via halogen
substitutions, which afforded new anti-C. difficile agents with ultrapotent activities [MICs as low as 0.003 μg/mL
(0.007 μM)] that surpassed the activity of vancomycin against C. difficile clinical isolates. The most promising
compound in the series, HSGN-218, is nontoxic to mammalian
colon cells and is gut-restrictive. In addition, HSGN-218 protected mice from CDI recurrence. Not only does this work provide
a potential clinical lead for the development of C.
difficile therapeutics but also highlights dramatic
drug potency enhancement via halogen substitution.
Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE) have been deemed as serious threats by the CDC. Many chronic MRSA and VRE infections are due to biofilm formation. Biofilm are considered to be between 10–10,000 times more resistant to antibiotics, and therefore new chemical entities that inhibit and/or eradicate biofilm formation are needed. Teichoic acids, such as lipoteichoic acids (LTAs) and wall teichoic acids (WTAs), play pivotal roles in Gram-positive bacteria’s ability to grow, replicate, and form biofilms, making the inhibition of these teichoic acids a promising approach to fight infections by biofilm forming bacteria. Here, we describe the potent biofilm inhibition activity against MRSA and VRE biofilms by two LTA biosynthesis inhibitors HSGN-94 and HSGN-189 with MBICs as low as 0.0625 µg/mL against MRSA biofilms and 0.5 µg/mL against VRE biofilms. Additionally, both HSGN-94 and HSGN-189 were shown to potently synergize with the WTA inhibitor Tunicamycin in inhibiting MRSA and VRE biofilm formation.
The rise of antibiotic-resistant infections has been well documented and the need for novel antibiotics cannot be overemphasized. US FDA approved antibiotics target only a small fraction of bacterial cell wall or membrane components, well-validated antimicrobial targets. In this review, we highlight small molecules that inhibit relatively unexplored cell wall and membrane targets. Some of these targets include teichoic acids-related proteins (DltA, LtaS, TarG and TarO), lipid II, Mur family enzymes, components of LPS assembly (MsbA, LptA, LptB and LptD), penicillin-binding protein 2a in methicillin-resistant Staphylococcus aureus, outer membrane protein transport (such as LepB and BamA) and lipoprotein transport components (LspA, LolC, LolD and LolE). Inhibitors of SecA, cell division protein, FtsZ and compounds that kill persister cells via membrane targeting are also covered.
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