A commonly expressed concern about building new antibiotics on the scaffolds of failing first-generation compounds is that the new drugs typically target the same molecular pathways as the originals and therefore microbes resistant to the old compound will rapidly become resistant to the new ones. Dr. Jon Thorson, a pharmaceutical scientist at University of Wisconsin-Madison, sees it differently (see also Decorating old drugs to combat resistance).
"Antibiotics target elements unique to the life of the pathogenic bacteria and regardless of whether the antibiotic hits a newly discovered or more classical antibiotic target, microbes counter by mutating the antibiotic target to prohibit the antibiotic from binding or by picking up genes that encode for enzymes to inactivate the antibiotic via chemical modification or pump the antibiotic out of the cell," he says. "A next-generation antibiotic must then be able to bind the mutated target and/or not be recognized by the antibiotic-inactivating machinery.
"To stay ahead in this constant struggle, innovative strategies to rapidly generate and screen variants of 'new' or old antibiotics are needed," he continues. "Moreover, as exemplified by the lipoglycopeptides, structural modifications of existing antibiotic scaffolds can actually redirect the drug to a new biological target."
