Inhibitors of Bacterial Swarming Behavior

Abstract

Bacteria can migrate in groups of flagella-driven cells over semisolid surfaces. This coordinated form of motility is called swarming behavior. Swarming is associated with enhanced virulence and antibiotic resistance of various human pathogens and may be considered as favorable adaptation to the diverse challenges that microbes face in rapidly changing environments. Consequently, the differentiation of motile swarmer cells is tightly regulated and involves multi-layered signaling networks. Controlling swarming behavior is of major interest for the development of novel anti-infective strategies. In addition, compounds that block swarming represent important tools for more detailed insights into the molecular mechanisms of the coordination of bacterial population behavior. Over the past decades, there has been major progress in the discovery of small-molecule modulators and mechanisms that allow selective inhibition of swarming behavior. Herein, an overview of the achievements in the field and future directions and challenges will be presented.

Keywords: flagella; interactions; motility; natural products; quorum sensing.

Figure 1

AI‐2 signaling and inhibition of signal synthesis through LuxS by the fimbrolide (1). The AI‐2 signal is R‐THMF in enterobacteria and the boric acid ester of S‐THMF for Vibrio species.

Figure 2

AHL‐based quorum sensing in enterobacteria (left) and Pseudomonas aeruginosa (right) and corresponding inhibitors that lead to inhibition of swarming motility.

Figure 3

a) Covalent inhibition of LasR by the 3‐oxo‐C12‐HSL analogue ICT‐F (6) causing reduction in swarming motility in P. aeruginosa. Quorum sensing and swarming inhibitors b) curcumin and c) phytol which causes down‐regulation of flhDC expression.

Scheme 1

The native metabolites HHQ (15) and PQS (14) and synthetic derivatives with swarming inhibitory activity.

Figure 4

Inhibition of swarming by histidine kinase inhibitors targeting the two‐component system GacSA.

Scheme 2

Antibiotics inhibiting swarming at sublethal concentrations.

Scheme 3

Examples of secondary plant metabolites with swarming‐inhibitory activity.

Scheme 4

Drugs with off‐target effects that inhibit swarming behavior.

Figure 5

Surfactants controlling swarming behavior of P. aeruginosa. a) Biosynthesis of rhamnolipids and swarming pattern of genetic knockout strains of the indicated biosynthesis genes. b) Synthetic surfactants modulating or inhibiting swarming motility of P. aeruginosa.

Figure 6

Flagellar motor assembly of H⁺‐ and Na⁺‐driven flagella and compounds interfering with motor function causing swarming inhibition.

Figure 7

Swarming and bioavailability of ferric iron. a) Avaroferrin produced by Shewanella algae blocks iron‐dependent swarming motility of Vibrio alginolyticus. b) Chelation of ferric iron by the ICDH‐coumarin 42 switches off RssAB two‐component system signaling and thereby triggers swarming.