Exploiting quorum sensing inhibition of the natural products fimbrolide and elegaphenone in gram-negative bacteria
Final Report Abstract
Natural products represent a potent source for novel antibiotics. In fact, many compounds have been deciphered decades ago but their mode of action still remains elusive. Given the current threat of multiresistant bacteria, these molecules represent an untapped source for new drugs. One natural strategy exploited by natural compounds is not the killing of bacteria but the inhibition of their communication, termed quorum sensing (QS). QS is essential to coordinate virulence, biofilm formation and bioluminescence. Fimbrolides have been discovered as QS inhibitors and we previously identified LuxS, a regulator of QS bioluminescence, as dedicated target in V. harveyj. In order to expand the utility of these molecules to kill pathogenic bacteria we aimed to elucidate the binding mode to LuxS of S. typhimurium via a co-crystal structure. However, after expression and crystallization of this protein we realized that contrary to the V. harveyj homolog, S. typhimurium LuxS does not bind fimbrolides. This unfortunately prevented the design of novel compounds which we nevertheless attempted by random chemical modifications. Encouragingly, some of the molecules were potent bioluminescence inhibitors of V. harveyj and will thus be included in future screens against pathogenic bacteria. Elegaphenone, another neglected natural product, turned out to be a potent inhibitor of P. aeruginosa virulence and was thus subject to in-depth mode of action analysis. We synthesized several derivatives and probes utilizing the intrinsic photoreactivity of the benzophenone core scaffold. Interestingly, the transcriptional regulator AlgP appeared as major hit and could be validated with transposon and whole proteome analysis. These studies consolidate a mode of action by which elegaphenone binding to AlgP reduces the expression of a pyocyanin transporter which in turn reduces the extracellular levels of this toxin. Although not directly linked to QS, this mechanism represents an attractive starting point for novel anti-virulence compounds.
Publications
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"The natural product elegaphenone potentiates antibiotic effects against Pseudomonas aeruginosa", Angew. Chem. Int. Edit., 2019, 58, 8581-8584
Zhao, W., Cross, A.R., Crow-McAuliffe, C., Weigert-Munoz, A., Csatary, E.E., Solinski, A.E., Krysiak, J., Goldberg, J.B., Wilson, D.N., Medina, E., Wuest, W.M., Sieber, S.A
