Design, Synthesis and Activity Evaluation Against Drug-Resistant Bacteria of 6'-Amidine Modified Aminoglycoside Derivatives

The issue of bacterial resistance has become a matter of significant concern globally, prompting extensive research into the development and clinical application of aminoglycoside antibiotics (AGAs) as a crucial antibacterial therapy. One of the primary mechanisms contributing to aminoglycoside antibiotic resistance is the action of aminoglycoside modifying enzymes (AMEs), which modify aminoglycoside antibiotics and consequently confer drug resistance. Chemical modification of the AME action site can eliminate functional groups vulnerable to AMEs, thus improving drug resistance. This study involves the introduction of alpha-hydroxy-gamma-aminobutyric acid and amidine to the 1 and 6 ' positions of sisomicin, respectively, to produce a range of 6 '-amidine modified sisomicin derivatives of AGAs. The research evaluates the antibacterial activity, absorption, distribution, metabolism, and excretion (ADME) properties, pharmacokinetic properties, cytotoxicity, nephrotoxicity, and drug resistance of AGAs. The outcomes of this study are significant in terms of enriching the structural understanding of aminoglycosides, providing insight into their structure-activity relationship, and producing new AGAs with high antibacterial activity, low ototoxicity, and nephrotoxicity. A series of new aminoglycoside derivatives AGA-x were obtained by introducing alpha-hydroxy-gamma-aminobutyric acid and amidine to the 1 and 6 ' positions of sisomicin, respectively, with excellent antibacterial activity, favorable ADME and pharmacokinetic properties, comparable cytotoxicity, and drug resistance characteristics to plazomicin. It is of great significance to develop new aminoglycosides, expand the structural diversity and further study the structure-activity relationship. image