Singly Modified Amikacin and Tobramycin Derivatives Show Increased rRNA A‐Site Binding and Higher Potency against Resistant Bacteria

Abstract

Semi-synthetic derivatives of clinically useful aminoglycosides, tobramycin and amikacin, were prepared by selectively modifying their 6″ position with a variety of hydrogen bond donors and acceptors. Their binding to the rRNA A-site was probed using an in vitro FRET-based assay and their antibacterial activity against several resistant strains (e.g., P. aeruginosa, K. pneumonia, MRSA) was quantified by determining minimum inhibitory concentrations (MICs). The most potent derivatives were evaluated for their eukaryotic cytotoxicity. Most analogs displayed greater affinity for the bacterial A-site compared to the parent compounds. Although most tobramycin analogs exhibited no improvement antibacterial activity, several amikacin analogs showed potent and broad-spectrum antibacterial activity against resistant bacteria. Derivatives tested for eukaryotic cytotoxicity exhibited minimal toxicity, similar to the parent compounds.

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 ].…”

Overcoming Aminoglycoside Enzymatic Resistance: Design of Novel Antibiotics and Inhibitors

“…The emergence of resistance towards the first generation of aminoglycosides led to increased efforts to identify similar antibiotics that were not susceptible to resistance [ 53 , 54 , 55 , 56 , 57 , 58 ]. From a conceptual point of view, one of the most simple and straightforward strategies to generate new derivatives that are not susceptible to enzymatic inactivation relies on the modification or elimination of those functional groups (OH/NH 2 ) that can be altered by the enzyme.…”

Carbon isotope labeling of carbamates by late-stage [11C], [13C] and [14C]carbon dioxide incorporation

“…The procedure was also applied for the 14 C and 11 C labeling of N-Boc protected Tobramycine derivative 26, 24 on a nonpharmacophoric position, according to previous SAR studies. 25 The SAW approach allowed to isolate the carbamates in 35% and 68 ± 2% d.c. RCY, respectively. In all cases, consistent high Am and radiochemical purities for both radioisotopes were obtained.…”