Chelation in Antibacterial Drugs: From Nitroxoline to Cefiderocol and Beyond

Abstract

In the era of escalating antimicrobial resistance, the need for antibacterial drugs with novel or improved modes of action (MOAs) is a health concern of utmost importance. Adding or improving the chelating abilities of existing drugs or finding new, nature-inspired chelating agents seems to be one of the major ways to ensure progress. This review article provides insight into the modes of action of antibacterial agents, class by class, through the perspective of chelation. We covered a wide scope of antibacterials, from a century-old quintessential chelating agent nitroxoline, currently unearthed due to its newly discovered anticancer and antibiofilm activities, over the commonly used antibacterial classes, to new cephalosporin cefiderocol and a potential future class of tetramates. We show the impressive spectrum of roles that chelation plays in antibacterial MOAs. This, by itself, demonstrates the importance of understanding the fundamental chemistry behind such complex processes.

Repurposing of the antibiotic nitroxoline for the treatment of mpox

“…Nitroxoline inhibits bacterial growth by chelating cations that are required by bacterial metalloenzymes, and the addition of cations such as Mg 2+ and Mn 2+ abrogates its antibacterial activity 40 . In contrast, the addition of Mg 2+ , Mn 2+ , or other divalent cations did not affect the antiviral activity of nitroxoline (Figure 3A,B) indicating a different mode of antiviral action.…”

Tetramate derivatives by chemoselective Dieckmann ring closure ofallo-phenylserines, and their antibacterial activity

“…The importance of metal chelation in these systems has recently become increasingly apparent and has been reviewed. 22,23…”

Repurposing of the antibiotic nitroxoline for the treatment of mpox

“…Nitroxoline inhibits bacterial growth by chelating cations that are required by bacterial metalloenzymes, and the addition of cations such as Mg 2+ and Mn 2+ abrogates its antibacterial activity [Repac Antić et al, 2022]. In contrast, the addition of Mg 2+ , Mn 2+ , or other divalent cations did not affect the antiviral activity of nitroxoline (Figure 3A,B) indicating a different mode of antiviral action.…”