Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance

Abstract

The rapid evolution and dissemination of antibiotic resistance among bacterial pathogens are outpacing the development of new antibiotics, but antivirulence agents provide an alternative. These agents can circumvent antibiotic resistance by disarming pathogens of virulence factors that facilitate human disease while leaving bacterial growth pathways - the target of traditional antibiotics - intact. Either as stand-alone medications or together with antibiotics, these drugs are intended to treat bacterial infections in a largely pathogen-specific manner. Notably, development of antivirulence drugs requires an in-depth understanding of the roles that diverse virulence factors have in disease processes. In this Review, we outline the theory behind antivirulence strategies and provide examples of bacterial features that can be targeted by antivirulence approaches. Furthermore, we discuss the recent successes and failures of this paradigm, and new developments that are in the pipeline.

Figure 1:. The rise of antivirulence approaches

The number of antivirulence publications and citations is sharply increasing over time. Web of Science (Thomson Reuters) was queried with the following search terms: “antivirulence” OR “anti-virulence” OR “virulence inhibition” OR “virulence inhibitor” OR “virulence factor inhibition”.

Figure 2:. Antivirulence agents targeting secreted and surface-exposed virulence factors

Overview of pathogenic secreted and surface-exposed virulence factors and inhibitors. Antivirulence agents highlighted yellow or red are FDA approved or in clinical trials, respectively. LF/LT = lethal factor/toxin, EF/ET = edema factor/toxin, CM = cellular membrane, MOM = mycolic outer membrane, PG = peptidoglycan, AG = arabinogalactan, LAM = lipoarabinomannan, scFv = single chain variable fragment, T3SS = type III secretion system.

Figure 3:. Quorum sensing and inhibition in model Gram-positive and Gram-negative pathogens

QS pathways and inhibition in the model Gram-positive and Gram-negative organisms S. aureus (A) and P. aeruginosa (B), respectively (adapted from Papenfort and Bassler, Figure 3). Synthases and exporters (black filling) produce autoinducer (AI) that signal through receptors (gray filling). Activated receptors globally modulate gene expression including many virulence factors. Selected examples of QS inhibitors that block receptors are shown. Note that P. aeruginosa produces homoserine lactone (HSL) and quinolone-based AI and S. aureus produces cyclic peptide-based AI. QS feedback loops and crosstalk between pathways is omitted for simplicity. AIP = autoinducing peptide, OM = outer membrane, PG = peptidoglycan, IM = inner membrane.