Next-generation glycopeptide antibiotics:Designs to overcome inherited and non-inherited resistance and insights into their mechanisms of action

Abstract

With the rise of antimicrobial resistance (AMR), bacteria such as Staphylococcus aureus, Enterococci and Acinetobacter baumannii have become refractory to the use of last-line antibiotics such as vancomycin and colistin. This has prompted the World Health Organization to classify these vancomycin- and carbapenem- resistant pathogens as high and critical priority pathogens for drug discovery respectively. This form of resistance termed “inherited resistance” has limited the arsenal of available drugs. To exacerbate the problem, bacteria slow down their metabolic activity (e.g. persister cells) or form colonies called biofilms that are also recalcitrant to antibiotic usage. These “non-inherited forms of resistance” have also complicated treatment modalities prompting alternative forms of drug discovery. This thesis addresses these challenges by the design and development of novel semi-synthetic vancomycin derivatives.