Abstract
Plazomicin is currently the only next-generation aminoglycoside approved for clinical use that has the potential of evading the effects of widespread enzymatic resistance factors. However, plazomicin is still susceptible to the action of the resistance enzyme AAC(2′)-Ia from Providencia stuartii. As the clinical use of plazomicin begins to increase, the spread of resistance factors will undoubtedly accelerate, rendering this aminoglycoside increasingly obsolete. Understanding resistance to plazomicin is an important step to ensure this aminoglycoside remains a viable treatment option for the foreseeable future. Here, we present three crystal structures of AAC(2′)-Ia from P. stuartii, two in complex with acetylated aminoglycosides tobramycin and netilmicin, and one in complex with a non-substrate aminoglycoside, amikacin. Together, with our previously reported AAC(2′)-Ia-acetylated plazomicin complex, these structures outline AAC(2′)-Ia’s specificity for a wide range of aminoglycosides. Additionally, our survey of AAC(2′)-I homologues highlights the conservation of residues predicted to be involved in aminoglycoside binding, and identifies the presence of plasmid-encoded enzymes in environmental strains that confer resistance to the latest next-generation aminoglycoside. These results forecast the likely spread of plazomicin resistance and highlight the urgency for advancements in next-generation aminoglycoside design.
Highlights
Plazomicin is currently the only next-generation aminoglycoside approved for clinical use that has the potential of evading the effects of widespread enzymatic resistance factors
At present time widespread aminoglycoside resistance has curtailed usage, where aminoglycoside modifying enzymes (AMEs) are the most significant factors attributed to antibiotic inactivation[5,6]
Its dimeric structure has an identical fold to another enzyme in this subclass, AAC(2′)-Ic from Mycobacterium tuberculosis, which shares a 55% sequence similarity and 32% sequence identity to AAC(2′)-Ia (Fig. 1a)[19]
Summary
Plazomicin is currently the only next-generation aminoglycoside approved for clinical use that has the potential of evading the effects of widespread enzymatic resistance factors. Some of the first iterations of semisynthetic aminoglycosides, including amikacin, netilmicin, and isepamicin, introduced bulky extensions to the N1-position of kanamycin, sisomicin, and gentamicin B, respectively (see Supplementary Fig. S1 online)[7,8] These antibiotics would prove to be more therapeutically viable than their precursor by eluding the effects of some AMEs through their inability to bind to these resistance enzymes, though they maintained affinity for their target, the 16S ribosomal A s ite[7]. These types of analyses have revealed that aminoglycosides bind to AMEs and the ribosome in their lowest energy conformation with little changes to the antibiotic, utilizing similar motifs for hydrogen bonding, while significantly varying in their van der Waals surface interactions[9,11,12] Together, these techniques can pinpoint key features of aminoglycoside design that can allow them to evade the action of AME’s that their parent compounds were previously susceptible to. These additions to the sisomicin aminoglycoside skeleton have reduced the number of enzymes able to selectively bind and modify plazomicin to just one, AAC(2′)-Ia14,15
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