Anti-infectives/Anti-virulence
Current treatment of human bacterial infections depends on bactericidal and bacteriostatic antibiotics whose long-term effectiveness is limited by the inevitable development of drug resistance and the potential to devastate the host commensal microbial community, leading to the demise of their effectiveness. An alternative approach to combat bacterial pathogens is the use of anti-infective drugs that selectively disrupt pathways that mediate virulence, such as regulation of pathogenesis genes. Compounds that do not disrupt survival or growth should be less likely to generate resistance than traditional antibiotics. Ideally, these reagents should not disrupt the beneficial microbiota, host metabolism, and should not cause harmful side effects.
In simpler terms, the human body actually contains more microbial cells than mammalian ones. We naturally live in peaceful, mutually beneficial coexistence with these organisms. Trouble arises when this balance is disrupted and those microbial organisms that possess harmful characteristics begin to proliferate. Antibiotics are designed to kill microbes indiscriminately. Whereas, anti-infectives are not designed to kill microbes but rather to prevent the expression of their harmful features.
Our Lab has identified and validated the utility of selective anti-virulence compounds that efficiently inhibited the synthesis of molecules required for the activation of the MvfR-dependent QS regulatory pathway of the human opportunistic pathogen Pseudomonas aeruginosa. Such reagents should have significant clinical utility in treating acute and chronic P. aeruginosa infections. In addition, several of these compounds have a broad-spectrum anti-infective effect against several clinically significant human pathogens.
Anti-virulence drugs should reduce antibiotic use and, ultimately, decrease the development of antibiotic resistance, as they should not impose strong selective pressure on bacteria that favors the evolution of mechanisms of resistance and persistence. Because anti-virulence compounds do not affect bacterial cell viability, they should not disrupt beneficial microbiota.
The discovery of the role of MvfR in mediating antibiotic tolerance and persister cell formation also opened the way for the study and inhibition of this highly important currently untreatable phenomenon. Interruption of the pro-acute and pro-persistence quorum sensing MvfR-regulated signals can be achieved in vivo also against multi-drug resistant clinical P. aeruginosa isolates. The applications of manipulating the function of this quorum sensing system for the development of alternative therapies to block virulence lead to the founding of Spero Therapeutics in 2013.