Research in the Sperandio laboratory is directed toward understanding how bacteria recognize the host, and how we can exploit this knowledge to interfere with bacterial infections. My laboratory reported that bacterial pathogens, such as enterohemorrhagic E. coli (EHEC), Salmonella typhimurium, Francisella tularensis, typical of the “super bugs”, exploit cell-to-cell signaling between the microbial flora and the host as a means to gage and recognize the host environment. This inter-kingdom signaling is predicated upon hormonal communication, and utilizes the host epinephrine and/or norepinephrine (NE) stress hormones and a bacterial aromatic hormone-like signal named autoinducer-3 (AI-3).
The hormones epinephrine and NE play a central role in stress responses in mammals. Mammalian adrenergic receptors are G-coupled protein receptors (GPCRs), bacteria, however, sense these hormones through histidine sensor kinases (HKs). Upon sensing a defined environmental cue the HK autophosphorylates in a histidine residue, and then initiates a complex signaling cascade to regulate gene expression within the bacterial cell. We have also identified the QseC and QseE bacterial adrenergic receptors. In addition to sensing these host hormones, we showed that QseC also senses the bacterial chemical signal, AI-3, produced by the normal gastrointestinal (GI) microbial flora of humans. The QseC sensor is a receptor for both a bacterial and a host signal, integrating bacterial-host signaling at the biochemical level. Importantly, QseC homologues are present in at least 25 other important human and plant pathogens.
Our lab has also shown that inhibition of this signaling pathway, specifically the QseC sensor, by small molecules constitutes a novel approach to develop therapeutic strategies to hamper bacterial infections. Because QseC is clearly essential for the activation of the virulence in many bacterial pathogens, and mammals do not harbor HKs, inhibitors of bacterial HKs are attractive potential novel therapeutics due to their selective toxicity. We have screened UT Southwestern's 150,000 small molecule chemical library and, from the initial hits, developed a remarkably potent small molecule antagonist to QseC (lead compound LED209). This compound is highly selective for the bacterial QseC receptor, not acting in mammalian adrenergic receptors, and is non-toxic to mammalian cells. LED209 (at a concentration of only 5pM) effectively blocks QseC recognition of epinephrine and norepinephrine, successfully blocks virulence gene expression and pathogenesis in EHEC, S. typhimurium and F. tularensis in vitro and in vivo (during animal infections), but do not interfere with pathogen growth, which may lead to a milder evolutionary pressure towards development of drug resistance. In this approach to antimicrobial drug development, QseC antagonists confuse or obfuscate signaling between bacteria and the host, and unlike antibiotics, do not kill or hinder bacterial growth. Hence, QseC antagonists should be viewed as blockers of pathogenicity (anti-virulence drugs) rather than as antimicrobials.
There is an imminent need for development of novel treatments for infectious diseases, given that one of the biggest challenges to medicine in the foreseeable future is the emergence of microbial antibiotic resistance. The rapid mutation rate of bacteria allows them to develop resistance to virtually all known antibiotics. This threat to humans and their food sources is immediate, global and potentially catastrophic.