Inhibition of Aminoglycoside Acetyltransferase Resistance Enzymes by Metal Salts

Abstract

Aminoglycosides (AGs) are clinically relevant antibiotics used to treat infections caused by both Gram-negative and Gram-positive bacteria, as well as Mycobacteria. As with all current antibacterial agents, resistance to AGs is an increasing problem. The most common mechanism of resistance to AGs is the presence of AG-modifying enzymes (AMEs) in bacterial cells, with AG acetyltransferases (AACs) being the most prevalent. Recently, it was discovered that Zn 2؉ metal ions displayed an inhibitory effect on the resistance enzyme AAC(6=)-Ib in Acinetobacter baumannii and Escherichia coli. A minoglycosides (AGs) are broad-spectrum bactericidal antibiotics that are used clinically for the treatment of serious bacterial infections (1, 2). These antibiotics were originally isolated from Streptomyces and Micromonospora (3) and display activity against Gram-positive bacteria, aerobic Gram-negative pathogenic bacteria, and Mycobacteria. Since the discovery of streptomycin, the first-in-class AG isolated, many AGs have been discovered and developed with improved efficacy. This property has kept them clinically relevant despite their inherent oto-and nephrotoxicity. Currently, amikacin (AMK), gentamicin (GEN), and tobramycin (TOB) are the most commonly prescribed AGs for systemic administration in the United States against bacterial infections (see Fig. S1 in the supplemental material) (4). Another AG, kanamycin A (KAN), is also used systemically but only to treat resistant strains of Mycobacterium tuberculosis in patients who show no response to first-line antituberculosis treatments. Other AGs, such as neomycin B (NEO), are found in antibiotic ointment formulations for topical use (5).The increased importance and popularity of AGs have, unfortunately, led to lapses in antimicrobial stewardship. This has accelerated the development of resistance against AGs and reduced the effective agents available for combating ever-evolving pathogens. The most common mechanism of bacterial resistance to AGs is the acquisition of AG-modifying enzymes (AMEs) (6, 7). Based on the reactions that they catalyze, AMEs can be classified as AG N-acetyltransferases (AACs), AG O-phosphotransferases (APHs), or AG O-nucleotidyltransferases (ANTs), among which AACs are responsible for the majority of resistant infections. AACs modify AG substrates and disrupt their binding to the ribosome by transferring the acetyl group from acetyl coenzyme A (AcCoA) onto amine moieties of the AG scaffolds. Although most AACs are regiospecific and modify only a single amino group, the unique enhanced intracellular survival (Eis) protein upregulated in resistant M. tuberculosis strains is capable of acetylating AG substrates at several different positions (8)(9)(10).In an effort to overcome bacterial resistance, a large amount of time and money has been invested toward the development of inhibitors of these resistance enzymes. Most commonly, small organic molecules have been explored for this purpose. For example, in silico and high-throughput screening was used to ide...

Inhibition of Aminoglycoside 6′- N -Acetyltransferase Type Ib-Mediated Amikacin Resistance in Klebsiella pneumoniae by Zinc and Copper Pyrithione

“…1A and B). This result agrees with that recently observed in a similar study (22). We showed before that the chloride salt of Zn 2ϩ in combination with AMK induced inhibition of growth in Escherichia coli and Acinetobacter baumannii strains harboring aac(6=)-Ib; however, very high concentrations were required (19).…”

Co-selection of antibiotic and metal(loid) resistance in gram-negative epiphytic bacteria from contaminated salt marshes

“…This opposite effect may be due to the interference of metals with specific antibiotic resistance mechanisms. For instance, recent studies showed that Cu and Zn inhibit the activity of aminoglycoside acetyltransferases, which confer resistance to aminoglycosides (Li et al, 2015).…”

Comprehensive review of antimicrobial activities of plant flavonoids

“…Antibacterial action of flavonoid-metal complexes Havsteen (2002), in his voluminous paper on flavonoid properties, tried to explain the antibacterial activities of flavonoids. Since many studies showed the ability of flavonoids to chelate transition metal ions (Karlíčková et al 2015;Li et al 2015;Riha et al 2014;Samsonowicz et al 2017), he pointed out that many flavonoids could cause the inhibition of bacterial metal enzymes. This mechanism of action is common for many other antibacterial substances, including lactoferrin from human milk.…”