Investigating a novel photoactivatable diarylacetylene as an antimicrobial agent against Gram-positive bacteria

Abstract

The emergence of antibiotic resistance is a growing threat to human health, and therefore, alternatives to existing compounds are urgently needed. In this context, a novel fluorescent photoactivatable diarylacetylene has been identified and characterised for its antibacterial activity, which preferentially eliminates Gram-positive over Gram-negative bacteria. This compound effectively eliminates clinically relevant Gram-positive bacteria without the development of tolerance upon repeated subculturing. We noted that bacteria lacking oxidative damage repair pathways exhibited increased sensitivity. Activation of the diarylacetylene led to detectable intracellular oxidative stress and upregulation of reactive oxygen species (ROS) detoxification proteins, suggesting that the mechanism of antibacterial activity is linked to ROS production. Our experiments indicated that the tolerance observed in Gram-negative bacteria is attributed to their lipopolysaccharide-rich outer membrane. Strains with compromised outer membrane integrity demonstrated heightened susceptibility to the compound. Additionally, the removal of accumulated intracellular diarylacetylene is crucial for tolerance; with disruption of the non-specific AcrAB-TolC efflux pump resulting in increased susceptibility. This new diarylacetylene shows promise as an antibacterial agent against Gram-positive bacteria that can be activated in situ, potentially for the treatment of skin infections.