Table 3.

Main mechanisms of antibiotic resistance and effects of iron withdrawal

Resistance mechanism	Nature of resistance	Examples (reference)	Likely affected by iron withdrawal?
Antibiotic neutralization	Enzymes produced by microbes to modify/degrade antibiotic; rendering it inactive	β-lactam degradation and aminoglycoside modifications (Wright 2005); metallo-β-lactamase, and aminoglycoside acetyltransferase in A. baumannii	Presumably yes as enzyme induction requires RNA and protein synthesis utilizing iron dependent enzymes
Antibiotic target modification	Mutations providing altered non-sensitive microbial target	Mupirocin resistance in S. aureus from altered insensitive isoleucine-tRNA synthetase target (Liu et al. 2017)	Presumably yes as low iron can suppress Fe-dependent ribonucleotide reductase levels as needed for DNA synthesis and repair
Antibiotic Efflux Pumps	Reduced intracellular antibiotic concentration, exclusion from cell	Ciprofloxacin and other fluoroquinolone efflux in P. aeruginosa (Lubelski et al. 2007; Amaral et al. 2014)	Yes, iron withdrawal can affect energy production by iron-dependent enzymes and iron insufficiency causes membrane instability (Prasad et al. 2006)
Physical resistance to antibiotic delivery into microbes	Biofilm growth physically protecting microbes within biofilm	P. aeruginosa biofilm displays resistance (Gupta et al. 2016)	Yes, iron withdrawal can suppress biofilm formation and also disrupt established biofilm growth (Post et al. 2019)
Metabolic mutation; persister cells	Slower growth and reduced electron transport reduces antibiotic sensitivity	S. aureus small colony variants—hemin/menadione and thymidine auxotrophs display multiple resistance (Proctor et al. 1998, 2014)	Yes, deferiprone-Gallium active against S. aureus SCVs, particularly hemin auxotrophs (Richter et al. 2017)