Aminoglycoside modifying enzymes

Abstract

Aminoglycosides have been an essential component of the armamentarium in the treatment of lifethreatening infections. Unfortunately, their efficacy has been reduced by the surge and dissemination of resistance. In some cases the levels of resistance reached the point that rendered them virtually useless. Among many known mechanisms of resistance to aminoglycosides, enzymatic modification is the most prevalent in the clinical setting. Aminoglycoside modifying enzymes catalyze the modification at different −OH or −NH 2 groups of the 2-deoxystreptamine nucleus or the sugar moieties and can be nucleotidyltranferases, phosphotransferases, or acetyltransferases. The number of aminoglycoside modifying enzymes identified to date as well as the genetic environments where the coding genes are located is impressive and there is virtually no bacteria that is unable to support enzymatic resistance to aminoglycosides. Aside from the development of new aminoglycosides refractory to as many as possible modifying enzymes there are currently two main strategies being pursued to overcome the action of aminoglycoside modifying enzymes. Their successful development would extend the useful life of existing antibiotics that have proven effective in the treatment of infections. These strategies consist of the development of inhibitors of the enzymatic action or of the expression of the modifying enzymes. Keywordsantibiotic resistance; aminoglycoside; aminoglycoside modifying enzyme; acetyltransferase; nucleotidyltransferase; phosphotransferase; kinase; antisense; RNase P; RNase H; bacterial infection 1. A brief overview of aminoglycoside antibiotics General aspectsAminoglycoside antibiotics are a complex family of compounds characterized for having an aminocyclitol nucleus (streptamine, 2-deoxystreptamine, or streptidine) linked to amino sugars through glycosidic bonds. In addition, other compounds such as spectinomycin, which is an aminocyclitol not linked to amino sugars, or compounds that include the aminocyclitol fortamine are also included in this family (Bryskier, 2005;Veyssier and Bryskier, 2005). Aminoglycosides are primarily used in the treatment of infections caused by gram-negative aerobic bacilli, staphylococci, and other gram-positives (Yao and

The whole genome sequencing of Acinetobacter-calcoaceticus-baumannii complex strains involved in suspected outbreak in an Intensive Care Unit of a pediatric hospital

“…The analysis of aminoglycosides resistance in our survey indicated that ST195 isolates carry the genetic determinants aph(3")-Ib, aph(3')-Ic, aph(6)-Id [22] and armA 16S-RNAmethylase [23] and ST281 presented the same genes showed above with the addition of aadA1. These genetic determinants explained the resistance to all the aminoglycosides tested AK, GM, TO.…”

Class 1 integrons in non-clonal multidrug-resistant Acinetobacter baumannii from Iran, description of the new bla IMP-55 allele in In1243

“…AadA1 has aminoglycoside 3¢-adenylyltransferase activity which is associated with streptomycin and spectinomycin resistance. AacC1 gentamicin 3¢-acetyltransferase conveys resistance to gentamicin only (Ramirez et al, 2010). High prevalence of aacC1 gene associated with class 1 integron in MDR isolates may be due to inordinate prescription of aminoglycosides in clinical settings and might also be due to a clonal spread of one A. baumanni clone.…”

Limited genetic diversity and extensive antimicrobial resistance in clinical isolates of Acinetobacter baumannii in north-east Iran

“…Aminoglycoside resistance genes confer resistance to this class of antibiotics by different modifying enzymes, including phosphotransferases (aphA1 and aphA6), nucleotidyltransferases (aadA1 and aadB) and acetyltransferase (aacC1) (Ramirez & Tolmasky, 2010). In addition, intrinsic resistance to all these antibiotics could occur by means of general AdeABC efflux pumps (adeB) (Yoon et al, 2013).…”