Inhibitors of Aminoglycoside Resistance Activated in Cells

Abstract

The most common mechanism of resistance to aminoglycoside antibiotics entails bacterial expression of drug-metabolizing enzymes, such as the clinically widespread aminoglycoside N-6'-acetyltransferase (AAC(6')). Aminoglycoside-CoA bisubstrates are highly potent AAC(6') inhibitors; however, their inability to penetrate cells precludes in vivo studies. Some truncated bisubstrates are known to cross cell membranes, yet their activities against AAC(6') are in the micromolar range at best. We report here the synthesis and biological activity of aminoglycoside-pantetheine derivatives that, although devoid of AAC(6') inhibitory activity, can potentiate the antibacterial activity of kanamycin A against an aminoglycoside-resistant strain of Enterococcus faecium. Biological studies demonstrate that these molecules are potentially extended to their corresponding full-length bisubstrates by enzymes of the coenzyme A biosynthetic pathway. This work provides a proof-of-concept for the utility of prodrug compounds activated by enzymes of the coenzyme A biosynthetic pathway, to resensitize resistant strains of bacteria to aminoglycoside antibiotics.

Exploring structural motifs necessary for substrate binding in the active site of Escherichia coli pantothenate kinase

“…These applications include both in vitro and in-cell labelling of carrier proteins in polyketide and nonribosomal peptide synthesis, [17][18][19] as well as aminoglycoside resistance inhibitors activated by the CoA biosynthetic pathway. 20 Although a wide range of pantothenamide derivatives have been reported over the years, most of these derivatives are modified at the amine moiety and less is known about the effects of modifications at other positions. Given the current and potential utility of pantothenate derivatives, a greater understanding of their effect on PanK is beneficial to future chemical biology and medicinal chemistry research.…”

Understanding and overcoming aminoglycoside resistance caused by N-6′-acetyltransferase

“…112 As mentioned above, aminoglycoside-pantetheine analogues 19a-e have no detectable effect on the activity of AAC(6′)-Ii. Many pantetheine derivatives are known to be transformed by the CoA biosynthetic enzymes to the corresponding CoA-containing analogues.…”

“…Compounds 19a-e ( Figure 4D) which are bisubstrate analogs lacking the adenosine diphosphate group, were therefore synthesized but reported to show no significant inhibitory activity against AAC(6′)-Ii (up to 500 μM). 108,112 On the other hand, compound 20 which lacks the adenosine monophosphate moiety but retains one phosphate group, shows low micromolar activity. Analysis of the AAC(6′)-Ii crystal structures reveals 5 potential hydrogen bonding interactions between this phosphate groups and the enzyme.…”

Identification of an inhibitor of the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib] by glide molecular docking

“…Early efforts permitted to identify a multisubstrate inhibitor of an AAC(3’) 35 . Bisubstrate and bisubstrate-like inhibitors were later designed to target AAC(6’) enzymes but most showed low efficacy in vivo 24, 26–30, 34, 36, 37 . Antimicrobial peptides were also tested as inhibitors of aminoglycoside acetyltransefrases as well as aminoglycoside phosphotransferases 31 .…”