Restoring susceptibility to aminoglycosides: identifying small molecule inhibitors of enzymatic inactivation

Abstract

Growing resistance to antimicrobial medicines is a critical health problem that must be urgently addressed. Adding to the increasing number of patients that succumb to infections, there are other consequences to the rise in resistance like the compromise of several medical procedures and dental work that are heavily dependent on infection prevention. Since their introduction in the clinics, aminoglycoside antibiotics have been a critical component of the armamentarium to treat infections. Still, the increase in resistance and their side effects led to a decline in their utilization. However, numerous current factors, like the urgent need for antimicrobials and their favorable properties, led to renewed interest in these drugs. While efforts to design new classes of aminoglycosides refractory to resistance mechanisms and with fewer toxic effects are starting to yield new promising molecules, extending the useful life of those already in use is essential. For this, numerous research projects are underway to counter resistance from different angles, like inhibition of expression or activity of resistance components. This review focuses on selected examples of one aspect of this quest, the design or identification of small molecule inhibitors of resistance caused by enzymatic modification of the aminoglycoside. These compounds could be developed as aminoglycoside adjuvants to overcome resistant infections.

Fig. 1. Chemical structures of representative aminoglycosides. Representative structures of aminoglycosides, which contain an aminocyclitol nucleus (colored) linked to amino sugars through glycosidic bonds. Spectinomycin contains an aminocyclitol not linked to amino sugars.

Fig. 2. Strategies to reduce aminoglycoside modifying enzymes-mediated resistance to aminoglycoside antibiotics. The yellow circle points to the focus of this review article.

Fig. 3. Intracellular prodrug to active bisubstrate inhibitor conversion. Proposed pathway of intracellular conversion of a neamine-containing bisubstrate prodrug (inactive) to an active bisubstrate inhibitor by enzymes of the CoA biosynthetic pathway. The donor substrate in all three reactions is ATP. The region of the molecules modified in each enzymatic reaction is circled. The neamine is shown in blue.

Fig. 4. Chemical structures of scaffolds that originated Eis inhibitors. Analogs were generated changing substituents at the positions highlighted in color.

Fig. 5. Chemical structures of haloperidol (antipsychotic), azelastine (antihistamine), venlafaxine (antidepressant), chloroquine (antimalarial), mefloquine (antimalarial), and proguanil (antimalarial). Analogs were generated changing substituents at the positions highlighted in color. The yellow highlight indicates that the number of methylene groups can be modified.

Fig. 6. Chemical structure of the pyrrolidine pentamine scaffold compound with the most potent AAC(6′)-Ib-mediated acetylation inhibitory activity. The colored locations are those where different substituents were placed in the combinatorial library and analogs. The green region is modified in stereochemistry.

Fig. 7. Chemical structures of aminoglycoside O-phosphotransferase inhibitors. Left, the isoquinolinesulfamide scaffold (blue) was replaced by various chemical groups at the R position (highlighted in yellow). The compounds shown, H-7 and CKI-7 are competitive inhibitors (versus ATP) of APH(3′)-IIIa and the bifunctional AAC(6′)-Ie-APH(2′′)-Ia. Center, two pyrazolopyrimidine scaffolds (red) showing the R positions (highlighted in colors) used to insert various chemical groups. The compounds shown, 1-NA-PP1 and the parent compound PP1, are inhibitors of APH(3′)-Ia activity in vitro and reduce resistance in hyperpermeable E. coli. Right, compounds NL6 and NL8. Both compounds are inhibitors of APH(3′)-IIIa, and NL6 is also an APH(2′)-IVa inhibitor.