Several metal-based carbon monoxide-releasing molecules (CORMs) are active CO donors with established antibacterial activity. Among them, CORM conjugates with azole antibiotics of type [Mn(CO) 3 (2,2′-bipyridyl)(azole)] + display important synergies against several microbes. We carried out a structure−activity relationship study based upon the lead structure of [Mn(CO) 3 (Bpy)(Ctz)] + by producing clotrimazole (Ctz) conjugates with varying metal and ligands. We concluded that the nature of the bidentate ligand strongly influences the bactericidal activity, with the substitution of bipyridyl by small bicyclic ligands leading to highly active clotrimazole conjugates. On the contrary, the metal did not influence the activity. We found that conjugate [Re(CO) 3 (Bpy)(Ctz)] + is more than the sum of its parts: while precursor [Re(CO) 3 (Bpy)Br] has no antibacterial activity and clotrimazole shows only moderate minimal inhibitory concentrations, the potency of [Re(CO) 3 (Bpy)(Ctz)] + is one order of magnitude higher than that of clotrimazole, and the spectrum of bacterial target species includes Gram-positive and Gram-negative bacteria. The addition of [Re(CO) 3 (Bpy)(Ctz)] + to Staphylococcus aureus causes a general impact on the membrane topology, has inhibitory effects on peptidoglycan biosynthesis, and affects energy functions. The mechanism of action of this kind of CORM conjugates involves a sequence of events initiated by membrane insertion, followed by membrane disorganization, inhibition of peptidoglycan synthesis, CO release, and break down of the membrane potential. These results suggest that conjugation of CORMs to known antibiotics may produce useful structures with synergistic effects that increase the conjugate's activity relative to that of the antibiotic alone.

Hydrogen sulfide and carbon monoxide share the ability to be beneficial or harmful molecules depending on the concentrations to which organisms are exposed. Interestingly, humans and some bacteria produce small amounts of these compounds. Since several publications have summarized the recent knowledge of its effects in humans, here we have chosen to focus on the role of H2S and CO on microbial physiology. We briefly review the current knowledge on how bacteria produce and use H2S and CO. We address their potential antimicrobial properties when used at higher concentrations, and describe how microbial systems detect and survive toxic levels of H2S and CO. Finally, we highlight their antimicrobial properties against human pathogens when endogenously produced by the host and when released by external chemical donors.

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