Abstract
Antibiotic resistance is recognized as a growing healthcare problem. To address this issue, one strategy is to thwart the causal mechanism using an adjuvant in partner with the antibiotic. Aminoglycosides are a class of clinically important antibiotics used for the treatment of serious infections. Their usefulness has been compromised predominantly due to drug inactivation by aminoglycoside-modifying enzymes, such as aminoglycoside phosphotransferases or kinases. These kinases are structurally homologous to eukaryotic Ser/Thr and Tyr protein kinases and it has been shown that some can be inhibited by select protein kinase inhibitors. The aminoglycoside kinase, APH(3′)-IIIa, can be inhibited by CKI-7, an ATP-competitive inhibitor for the casein kinase 1. We have determined that CKI-7 is also a moderate inhibitor for the atypical APH(9)-Ia. Here we present the crystal structures of CKI-7-bound APH(3′)-IIIa and APH(9)-Ia, the first structures of a eukaryotic protein kinase inhibitor in complex with bacterial kinases. CKI-7 binds to the nucleotide-binding pocket of the enzymes and its binding alters the conformation of the nucleotide-binding loop, the segment homologous to the glycine-rich loop in eurkaryotic protein kinases. Comparison of these structures with the CKI-7-bound casein kinase 1 reveals features in the binding pockets that are distinct in the bacterial kinases and could be exploited for the design of a bacterial kinase specific inhibitor. Our results provide evidence that an inhibitor for a subset of APHs can be developed in order to curtail resistance to aminoglycosides.
Highlights
The waning prospect of an effective treatment for bacterial infections due to the emergence and spread of resistance to antibiotics in pathogens has been exacerbated by the lack of novel antibacterials being introduced to the market [1]
We show that the atypical aminoglycoside phosphotransferases or kinases (APHs), APH(9)-Ia, is affected by this protein kinase inhibitor
Paralleling the APH(39)-IIIa result, CKI-7 was found to inhibit APH(9)-Ia (Ki = 159611 mM) in a competitive fashion with respect to ATP, 2.5 times less effectively. These results suggest that the CKI-7 scaffold may be exploited for the development of broad-spectrum APH inhibitors
Summary
The waning prospect of an effective treatment for bacterial infections due to the emergence and spread of resistance to antibiotics in pathogens has been exacerbated by the lack of novel antibacterials being introduced to the market [1].
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