A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus.

Treatment of Staphylococcus aureus infections is complicated by the development of antibiotic tolerance, a consequence of the ability of S. aureus to enter into a nongrowing, dormant state in which the organisms are referred to as persisters. We report that the clinically approved anthelmintic agent bithionol kills methicillin-resistant S. aureus (MRSA) persister cells, which correlates with its ability to disrupt the integrity of Gram-positive bacterial membranes. Critically, bithionol exhibits significant selectivity for bacterial compared with mammalian cell membranes. All-atom molecular dynamics (MD) simulations demonstrate that the selectivity of bithionol for bacterial membranes correlates with its ability to penetrate and embed in bacterial-mimic lipid bilayers, but not in cholesterol-rich mammalian-mimic lipid bilayers. In addition to causing rapid membrane permeabilization, the insertion of bithionol increases membrane fluidity. By using bithionol and nTZDpa (another membrane-active antimicrobial agent), as well as analogs of these compounds, we show that the activity of membrane-active compounds against MRSA persisters positively correlates with their ability to increase membrane fluidity, thereby establishing an accurate biophysical indicator for estimating antipersister potency. Finally, we demonstrate that, in combination with gentamicin, bithionol effectively reduces bacterial burdens in a mouse model of chronic deep-seated MRSA infection. This work highlights the potential repurposing of bithionol as an antipersister therapeutic agent.

Epoxy Isonitriles, A Unique Class of Antibiotics: Synthesis of Their Metabolites and Biological Investigations.

Epoxy isonitrile containing natural products often possess specific and potent antibacterial activity against Gram-positive pathogens. This scaffold, however, is extremely labile under acidic and basic conditions, undergoing a Payne rearrangement to produce a stable epoxy ketone metabolite and releasing hydrogen cyanide. We synthesized and performed biological assays with epoxy ketone containing metabolites and identified that the epoxy isonitrile moiety is pertinent for biological activity. Serendipitously, we discovered an α,ß-unsaturated epoxy ketone analogue that exhibited moderate activity against Staphylococcus aureus.

Total Synthesis and Antibacterial Investigations of 1-Hydroxyboivinianin A.

Synthetic investigations of natural products has been instrumental in the development of novel antibacterial small molecules. 1-hydroxyboivinianin A, a lactone containing phenolic bisabolane isolated from marine sediment, has reported antibacterial activity against the aquatic pathogen Vibrio harveyi. The total synthesis of 1-hydroxyboivinianin A and its enantiomer was completed in a six-step sequence in 42 % overall yield. The synthesis leveraged a key diastereoselective nucleophilic addition with chiral imidazolidinone to establish the benzylic tertiary alcohol and intramolecular Horner-Wadsworth Emmons to furnish the lactone. Both enantiomers were found to have negligible antibacterial activity against a panel of gram-positive and negative bacteria and minimal antifungal activity against phytopathogens. Investigations of a possible in vitro lactone hydrolysis to produce an inactive linear acid led to the discovery of a spontaneous cyclization, suggesting the lactone is resistant to hydrolysis and the lactone is not degrading to produce an inactive species.

Using membrane perturbing small molecules to target chronic persistent infections.

After antibiotic treatment, a subpopulation of bacteria often remains and can lead to recalcitrant infections. This subpopulation, referred to as persisters, evades antibiotic treatment through numerous mechanisms such as decreased uptake of small molecules and slowed growth. Membrane perturbing small molecules have been shown to eradicate persisters as well as render these populations susceptible to antibiotic treatment. Chemotype similarities have emerged suggesting amphiphilic heteroaromatic compounds possess ideal properties to increase membrane fluidity and such molecules warrant further investigation as effective agents or potentiators against persister cells.

Hijacking the Bacterial Circuitry of Biofilm Processes via Chemical "Hot-Wiring": An Under-explored Avenue for Therapeutic Development.

Biofilm-associated infections are linked to chronic and recurring illnesses. These infections are often not susceptible to current antibiotic treatments because of the protective exocellular matrix and subpopulations of dormant or "persister" cells. Targeting bacterial circuitry involved in biofilm formation, including two-component systems, quorum sensing, polysaccharide structural integrity, and cyclic nucleotide signaling pathways, has the potential to expand the existing arsenal of therapeutics, thus catalyzing a second golden age of antibiotic development.