Bacterial metal-dependent pathways

Bacterial metal-dependent pathways are a broad set of essential biological processes that utilize transition metals—primarily iron, zinc, manganese, and copper—as critical cofactors for enzyme catalysis, protein structure, and gene regulation (Chandrangsu et al., 2017). These pathways are vital for bacterial survival and virulence, encompassing metal acquisition systems like siderophores, regulatory proteins such as the Ferric Uptake Regulator (Fur), and numerous metalloenzymes (Bush and Bradford, 2016). Key therapeutic targets within these pathways include LpxC, a zinc-dependent enzyme essential for Gram-negative lipid A biosynthesis, and peptide deformylase (PDF), which is required for protein maturation (Clements et al., 2002; Giglione et al., 2000). Additionally, metallo-beta-lactamases (MBLs) utilize zinc to degrade a wide range of beta-lactam antibiotics, making them major drivers of multi-drug resistance (Bush and Bradford, 2016). Drugs targeting these pathways include direct enzyme inhibitors, such as PDF and LpxC inhibitors, and siderophore-drug conjugates like cefiderocol, which exploit iron transport systems to bypass the bacterial outer membrane (Zhanel et al., 2019). Despite their potential, drug development faces challenges such as achieving selectivity to avoid inhibiting human metalloenzymes and addressing the bacteria's ability to adapt through redundant metal-scavenging mechanisms.

Other names

Bacterial metal homeostasisBacterial metallo-pathwaysBacterial metal metabolismMetal-dependent bacterial enzymesBacterial metal-dependent pathway

Inhibition of essential bacterial metalloenzymes (e.g., LpxC, PDF), inhibition of metallo-beta-lactamases to restore antibiotic activity, and exploitation of metal transport systems for targeted drug delivery (siderophore-drug conjugates).