BACKGROUND:  Antibiotics are an important class of pharmaceuticals routinely used to treat a number of bacterial infections. However, upon exposure to antibiotics (such as penicillin), a bacterial strain develops drug resistance over time. Therefore, new antibiotics or ways to enhance current antibiotic agents are continuously needed. Until recently, conventional drug discovery methods have provided new antibiotics the ability to act upon these resistant bacteria. However, as a result of the increasing number of resistant bacteria strains and the limited number of known motifs for antibiotics, current drug discovery methodology is not yielding sufficient new antibiotic agents. A relatively new method of identifying potential ways to combat antibiotic resistance is the identification of bacterial genes that can be inactivated in order to increase the susceptibility of the bacterial cell to antibiotics. Several isolated examples of these methods can be found in the literature, but there has not been a systematic way to identify these genetic targets.

INNOVATION:  Researchers at UCLA have identified a high-throughput screening method that can simultaneously identify a large number of genes that when inactive, can increase the susceptibility of bacteria to antibiotics. Small molecules could then be designed to act as inhibitors that would render the desired gene(s) inactive. Therefore, these inhibitors would act as co-antibiotics (pharmaceutical agents that enhance antibiotic activity) and allow appropriate antibiotic treatments to work effectively.

POTENTIAL APPLICATIONS 

• Enables the rapid discovery of a multitude of gene targets
• Potential to find a variety of small molecule inhibitors that could cause desired gene inactivation and increased sensitivity of pathogenic bacteria to antibiotics.

ADVANTAGES

• High throughput screening that identifies gene targets more extensively, comprehensively, and rapidly
• Conventional antibiotic treatments could be used along with CO-antibiotics determined by this method

DEVELOPMENT-TO-DATE:  Proof-of-concept experiments have demonstrated that a large number of gene targets that increase antibiotic sensitivity could be quickly identified by screening a knockout collection of E. coli bacteria, each carrying a different inactive gene, against various concentrations of antibiotics. An analogous future study with Bacillus anthracis (the pathogen responsible for anthrax) will be pursued. Different classes of antibiotics, whether these sensitivity genes can also overcome resistance, and if bacteria possessing a combination of inactive targets experience additive sensitivities will be the subject of subsequent studies. Also in future work, collaboration with researchers to design suitable small molecule inhibitors will be pursued.

Reference: UCLA Case No. 2008-014