Exploiting Antibiotic Resistance Mechanisms to Combat Antibiotic Resistance

<p>Antimicrobial resistance is a global challenge and food animal production, including cattle production, is increasingly singled‐out as a significant contributor to emergence, amplification, persistence and dissemination of antimicrobial‐resistant bacteria. Regulatory controls and prudent‐use practices are the primary strategies used to control resistance, and these are probably very important to limit the emergence of resistance to new antibiotics. Once the prevalence of resistance has increased to a clinically relevant level, however, it is unclear how effective prudent use and regulatory control practices will be in the short‐term. This is primarily due to the fact that prudent use and regulatory controls rely on a very simple, but ineffective mechanism of “passive decay.” That is, we remove antibiotic selection pressure and “hope” that the resistant bacteria decline in prevalence. This is likely to happen eventually, but the rate of decline is a function of the fitness cost that is incurred by the bacteria for carrying resistance traits. Unfortunately, many traits cost little to retain in bacterial populations and there are numerous examples in the literature whereby removal of antibiotics has resulted in only limited declines in resistant populations of antibiotic resistant bacteria.</p>

<p>What we need is strategy to directly select against antibiotic resistant bacteria. Under this scenario we would target a highly prevalent antibiotic resistance trait and artificially induce a fitness cost on the host bacterium as the “price” for harboring the resistance trait. The fitness cost will make the bacteria less competitive so that the bacteria will rapidly diminish in prevalence, or they will shed the resistance trait. Unlike passive decline, active selection against antibiotic resistance would happen in a matter of days instead of years. There are several
candidate resistance traits to consider for this approach. Tetracycline efflux pumps are of particular interest because of their broad global distribution and because they are regulated so that their expression only occurs in the presence of tetracycline or a tetracycline analogue. Presumably, this tight regulation evolved to limit the fitness cost for expressing these traits when they are not needed. For the current proposal we developed a means to induce expression of tetracycline efflux pumps. We show that this method activates the resistance genes while not
having any antibacterial activity against susceptible bacteria. Feeding our inducer tetracycline resistance to dairy calves produced mixed results, but this has led to several additional ideas for developing this strategy.</p>