Chemical biology applied to the study of bacterial pathogens

Abstract

In recent years, chemical biology and chemical genomics have been increasingly applied to the field of microbiology to uncover new potential therapeutics as well as to probe virulence mechanisms in pathogens. The approach offers some clear advantages, as identified compounds (i) can serve as a proof of principle for the applicability of drugs to specific targets; (ii) can serve as conditional effectors to explore the function of their targets in vitro and in vivo; (iii) can be used to modulate gene expression in otherwise genetically intractable organisms; and (iv) can be tailored to a narrow or broad range of bacteria. This review highlights recent examples from the literature to illustrate how the use of small molecules has advanced discovery of novel potential treatments and has been applied to explore biological mechanisms underlying pathogenicity. We also use these examples to discuss practical considerations that are key to establishing a screening or discovery program. Finally, we discuss the advantages and challenges of different approaches and the methods that are emerging to address these challenges.

FIG 1

Critical steps in the pathogenicity of microbes and the small molecules that inhibit each step. Inhibitors discussed in this review (shown in red) target many aspects of pathogenesis (shown in black), including specific virulence factors and their regulation (steps 1 to 5, 10, and 13) and broader aspects of host-pathogen interactions (steps 6 to 9, 11 to 12, and 14).

FIG 2

Identifying and characterizing small-molecule inhibitors of pathogenesis require many considerations at each step of the process. The major strategies are outlined here and are discussed further in the text.

FIG 3

FPSS targets sigma B. Multiple stresses activate σ^B activity in B. subtilis. Energy stress is relayed via RsbPQ, environmental stress is relayed via the “stressosome” and RsbU, and low-temperature stress is relayed via an as-yet-unknown mechanism. Sensing of stress results in dephosphorylation of the RsbV anti-anti-sigma factor, allowing it to bind the RsbW anti-sigma factor, which in turn releases σ^B, to interact with RNAP and activate the σ^B regulon. Phosphorylated RsbV interacts poorly with RsbW, which is then free to bind σ^B, leading to low-level expression of the regulon. FPSS inhibits σ^B activity by driving equilibrium toward the state in which σ^B is bound to RsbW. SNP, single nucleotide polymorphism.

FIG 4

Pilicides affect both P pili and the type 1 pili, which have similar structures. Pili consist of several repeating subunits arranged in a helical structure. Subunits are translocated from the cytoplasm to the periplasm, where a chaperone (PapD or FimC) folds the protein, stabilizes it, and transfers it to the usher protein (PapC or FimD), which secretes the protein and incorporates it into the pilus structure. Pilicides inhibit formation of pili by preventing the chaperone from passing the subunit to the usher protein.