Novel peptides designed for use as antibiotic potentiators to combat drug-resistant bacterial pathogens.
Multidrug resistant (MDR) bacteria pose an ever-increasing threat due to ease of transmission and difficulty in treating the infections. Without significant advancements to current standards of care, antibiotic-resistant bacterial infections will become the leading cause of death, outpacing cancer-related deaths worldwide.
Antibiotic resistance is achieved mechanistically by the formation of efflux pumps in the outer membrane of the bacterial cell wall. These pumps directly bind to and shuttle drugs out of the cell by forming a channel. Efflux pumps significantly reduce the intracellular concentration of a given compound, thereby blocking the drug's intended activity. Toxic side effects have prevented the development of compounds that inhibit the drug-binding ability of efflux pumps. As described herein, a novel peptide has been designed to block the formation of the efflux pump, thereby restoring susceptibility to antibiotics which would otherwise be shuttled out of the cell.
This technology provides a novel, broad-spectrum antibiotic potentiators with therapeutic applications against several drug-resistant bacterial pathogens.
These peptides were designed from human sequence and targets the efflux pump, and prevents its oligomerization, thereby disabling the bacterium's ability to bind and shuttle drugs through the pump. In doing so, the peptides serve as antibiotic potentiators to increase/restore susceptibility to antibiotics that would otherwise be shuttled out of the bacterial cells.
Broad spectrum activity, increasing antibiotic sensitivity of several drug-resistant pathogens to several antibiotics. Novel mechanism of action which overcomes limitations/toxicity presented by agents designed to block drug binding sites on efflux pumps. Peptide designed from human sequence with specificity for a bacterial target; likelihood for toxicity in clinical applications is extremely low, and first use of novel peptides designed to manipulate the function of a naturally occurring efflux pump.
There have been other efforts to design efflux pump inhibitors but these studies have focused specifically on blocking drug binding sites located throughout the pump. These inhibitors are limited in scope due to there being multiple binding modes for different drugs, therefore an inhibitor that targets a specific binding site would only affect a subset of antibiotics. Additionally, these inhibitors have shown high levels of toxicity. In contrast, this peptide serves as an inhibitor of the entire efflux pump and therefore has the potential to increase efficacy of all antibiotics that would otherwise be bound and shuttled out of bacterial cells. Furthermore, the toxicity of this peptide is expected to be extremely low given that it specifically targets a component of bacterial membranes.
Apart from antibiotic resistance, other applications may include cancer therapeutics and environmental remediation.