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

Abstract

Aminoglycosides occupy a special niche amongst antibiotics in part because of their broad spectrum of action. Bacterial resistance is however menacing to render these drugs obsolete. A significant amount of work has been devoted to understand and overcome aminoglycoside resistance. This mini-review will discuss aminoglycoside-modifying enzymes (AMEs), with a special emphasis on the efforts to comprehend and block resistance caused by aminoglycoside 6′-N-acetyltransferase (AAC(6′)). Graphical AbstractResistance-causing AAC(6′)s have been studied and avoided in a number of ways. AAC(6′)-Ii surprises everyone with its complex allosteric behaviour.

Amikacin: Uses, Resistance, and Prospects for Inhibition

“…Following these developments, there was a period with relatively few additions to the field of aminoglycosides followed by another period characterized by new approaches that took advantage of the deeper understanding of different aspects of the biology and structure of aminoglycoside modifying enzymes as well as the advances in synthetic chemistry. As a consequence, numerous new generation aminoglycosides, also known as neoglycosides, started to be synthesized [ 19 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. Of the several neoglycosides existing in the pipeline, plazomicin (ACHN-490) ( Figure 2 ), which has been granted Breakthrough Therapy designation by the FDA in May 2017, is the one closest to be approved for human use [ 59 , 60 , 61 , 62 ].…”

“…Numerous kinds of compounds with robust inhibitory activity of AAC(6′)-I enzymes have been described and are listed in various comprehensive reviews [ 26 , 49 , 54 , 253 ]. An inhibitor of AAC(6′)-Ib was first designed by an NMR-fragment based-approach [ 254 ].…”

Strategies to Overcome the Action of Aminoglycoside-Modifying Enzymes for Treating Resistant Bacterial Infections

“…AG–AcCoA bisubstrate inhibitors of AAC(6′) were designed as potential drug candidates and for mechanistic studies (Figure 11A) [43]. NEA-AcCoA with linkers of varying length (1–5C) proved to be good inhibitors of A AC(6′)-Ii, A AC(6′)-Iy, and A AC(6′)-Ie/APH(2″)-Ia, with nanomolar to micromolar potencies [101].…”

“…SAR studies revealed that the adenosine is not essential, but potency drops dramatically if more than one phosphate is removed [105]. Crystal structures demonstrate several hydrogen bond donors positioned to interact with the negatively charged phosphates, supporting their importance in potent inhibitor binding [43]. Recently, another attempt to overcome poor cell membrane permeability includes the design of bisubstrate prodrugs consisting of only an AG with a pantetheine linker (Figure 11B) [106].…”

Identification of a Small Molecule Inhibitor of the Aminoglycoside 6’-N-Acetyltransferase Type Ib [AAC(6’)-Ib] Using Mixture-Based Combinatorial Libraries

“…Although considerable efforts are dedicated to designing new aminoglycosides that can overcome existing mechanisms of resistance [4, 9], other alternatives to counter the action of aminoglycoside modifying enzymes are being researched. They include the utilization of inhibitors of gene expression such as antisense oligonucleotide analogs [10-12], inhibitors of the enzymatic activity like those developed to overcome β-lactamase-mediated resistance to β-lactams [5, 13-18], or metal ion inhibitors of the acetylation reaction, which most probably act by protective chelation of the substrate antibiotic [19-22]. However, in spite of the efforts directed at designing inhibitors of aminoglycoside modifying enzymes or their expression, none are in use in the clinics yet [reviewed in 4, 5].…”