Abstract

Aminoglycoside acetyltransferases are important determinants of resistance to aminoglycoside antibiotics in most bacterial genera. In mycobacteria, however, aminoglycoside acetyltransferases contribute only partially to aminoglycoside susceptibility since they are related with low level resistance to these antibiotics (while high level aminoglycoside resistance is due to mutations in the ribosome). Instead, aminoglycoside acetyltransferases contribute to other bacterial functions, and this can explain its widespread presence along species of genus Mycobacterium. This review is focused on two mycobacterial aminoglycoside acetyltransferase enzymes. First, the aminoglycoside 2′-N-acetyltransferase [AAC(2′)], which was identified as a determinant of weak aminoglycoside resistance in M. fortuitum, and later found to be widespread in most mycobacterial species; AAC(2′) enzymes have been associated with resistance to cell wall degradative enzymes, and bactericidal mode of action of aminoglycosides. Second, the Eis aminoglycoside acetyltransferase, which was identified originally as a virulence determinant in M. tuberculosis (enhanced intracellular survival); Eis protein in fact controls production of pro-inflammatory cytokines and other pathways. The relation of Eis with aminoglycoside susceptibility was found after the years, and reaches clinical significance only in M. tuberculosis isolates resistant to the second-line drug kanamycin. Given the role of AAC(2′) and Eis proteins in mycobacterial biology, inhibitory molecules have been identified, more abundantly in case of Eis. In conclusion, AAC(2′) and Eis have evolved from a marginal role as potential drug resistance mechanisms into a promising future as drug targets.

Highlights

  • Specialty section: This article was submitted to Evolutionary and Genomic Microbiology, a section of the journal Frontiers in Microbiology

  • The aminoglycoside 2 -N-acetyltransferase [aminoglycoside acetyltransferases (AACs)(2 )], which was identified as a determinant of weak aminoglycoside resistance in M. fortuitum, and later found to be widespread in most mycobacterial species; AAC(2 ) enzymes have been associated with resistance to cell wall degradative enzymes, and bactericidal mode of action of aminoglycosides

  • We investigated the hypothesis of mycobacterial AAC(2 )-I enzymes having a role in cell wall metabolism, and a gene knock-out mutant of M. smegmatis deleted in aac(2 )-Id gene was constructed

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Summary

BACTERIAL RESISTANCE TO AMINOGLYCOSIDE ANTIBIOTICS

Aminoglycoside (AG) antibiotics (Box 1) have not been an exception to the fact that after their introduction in clinical practice, resistance has been recorded (Waglechner and Wright, 2017). We constructed a knock-out mutant of M. tuberculosis H37Rv deleted in the aac(2 )-Ic gene and observed that the mutant (named M. tuberculosis B1) was twofold more susceptible than the original wild-type strain to AGs containing a 2 -amino group such as gentamicin, tobramycin and dibekacin, and fourfold more susceptible to 6 -N-ethyl-netilmicin This indicated that the aac(2 )-Ic gene was being expressed in M. tuberculosis at a very low level, and that the AAC(2 )-Ic enzyme in M. tuberculosis would acetylate all these four AGs in the wild type strain; acetylated AGs would bind less efficiently to the ribosome, and the AAC(2 )-Ic enzyme would contribute to basal AG resistance in this species. Other in silico analysis revealed that AAC(2 )-Ic enzyme from M. tuberculosis could interact with ten other proteins (including a protein of a putative RND-like efflux pump), suggesting that inhibition of AAC(2 )-Ic could impact many other metabolic processes, conferring this enzyme with a relevant role in drug discovery of antituberculosis agents (Joshi et al, 2013)

THE Eis PROTEIN BECOMES A NOVEL AMINOGLYCOSIDE ACETYLTRANSFERASE
Finding Inhibitors of Eis Protein
CONCLUDING REMARKS
Findings
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