Antibiotic resistance has been a reality ever since the discovery of penicillin, yet with the overuse and misuse of antibiotics since the 1940s, antibiotic resistant infections are on the rise. Compounding the problem, over the past few decades antibiotic discovery and development has slowed. As a result, we are facing a crisis that is expected to create up to 10 million deaths globally by 2050 without urgent action. Selective pressure from antibiotics allows bacteria to generate a variety of resistance mechanisms, creating infections that can become severe and difficult or impossible to treat. Even many antibiotics deemed “last resort” are diminishing in effectiveness due to the emergence of highly resistant bacteria. Among these “last resort” antibiotics are glycopeptides that target bacterial cell wall synthesis in Gram-positive bacteria. Specifically, a precursor molecule to peptidoglycan synthesis, known as lipid II, is a common target for glycopeptides. To evade these antibiotics, the structure of lipid II is often modified to prevent glycopeptide binding. As bacterial resistance to the glycopeptides spreads, new antibiotics must be made to combat these differences in lipid II molecules. Most approaches to increasing the availability of new antibiotics fall into two categories—reducing time required for discovery and reducing cost of development. This research outlines a novel strategy for antibiotic design using directed evolution techniques. By taking advantage of selective processes, much like those that drive resistance, directed evolution can be used to develop novel antibiotics that meet both these needs. In addition to keeping up with the pace of antibiotic resistance, directed evolution also offers the opportunity to drive more personalized medicine in healthcare. Streamlining the discovery process may ultimately make it possible to take bacterial samples from patients and rapidly create antibiotics specific to their infections. Single domain antibodies, or nanobodies, are a class of molecules with favorable properties for use as antibiotics given their size, stability, and potential antigen specificity. This poster focuses on the directed evolution of nanobodies for use as antibacterial molecules against lipid II in Gram-positive bacteria. In addition, it outlines a unique antigen selection strategy that is expected to be broadly applicable to a wide range of Gram-positive pathogens.
Support or Funding Information
ASBMB Undergraduate Research Award 2021 and the Albion College Foundation for Undergraduate Research, Scholarship, and Creative Activity
