The Small-Molecule Language of Dynamic Microbial Interactions

Abstract

Although microbes are routinely grown in monocultures in the laboratory, they are almost never encountered as single species in the wild. Our ability to detect and identify new microorganisms has advanced significantly in recent years, but our understanding of the mechanisms that mediate microbial interactions has lagged behind. What makes this task more challenging is that microbial alliances can be dynamic, consisting of multiple phases. The transitions between phases, and the interactions in general, are often mediated by a chemical language consisting of small molecules, also referred to as secondary metabolites or natural products. In this microbial lexicon, the molecules are like words and through their effects on recipient cells they convey meaning. The current review highlights three dynamic microbial interactions in which some of the words and their meanings have been characterized, especially those that mediate transitions in selected multiphasic associations. These systems provide insights into the principles that govern microbial symbioses and a playbook for interrogating similar associations in diverse ecological niches.

Keywords: antibiotics; interspecies interactions; natural product; secondary metabolite; symbiosis.

Figure 1

Model for algal-roseobacter (Phaeobacter inhibens) interactions mediated by small molecules. Mutualistically beneficial metabolite exchanges are shown on the left and right with green arrows. Notably, Trp-IAA and Phe–phenylacetic acid form positive-feedback loops. DMSP, toward which roseobacter move via chemotaxis, can initiate the interaction, along with other nutrients. TDA protects the microassembly from possible pathogens. Metabolite exchanges in the parasitic phase are shown at top and bottom with red arrows. pCA triggers biosynthesis mostly of roseobacticide A and the siderophore roseobactin. Sinapic acid triggers biosynthesis of mostly roseobacticide C and roseochelin B, as well as other algicidal agents, sinacidins, sinatryptins, and sinamicins, which are not shown for clarity. Molecules are listed by phase. Abbreviations: DMSP, dimethylsulfoniopropionate; IAA, indole-3-acetic acid; pCA, p-coumaric acid; TDA, tropodithietic acid.

Figure 2

Model for IRLC legume–rhizobial interactions mediated by small molecules. (a) Plant root cells initiate the interaction via release of flavonoids; two examples, luteolin and daidzein, are shown. (b) Flavonoids trigger the release of Nod factors, for which a specific example from Sinorhizobium meliloti and a generalized structure are shown with points of diversification marked R¹ through R¹⁰. (c) In a complex, multistep process, Nod factors together with bacterial succinoglycans (not shown) and plant hormones, including indole-3-acetic acid and the cytokinin zeatin, trigger formation of shepherd’s crooks and infection threads, culminating in development of symbiosomes. (d,e) In IRLC legumes, plant-derived NCRs initiate terminal bacteroid differentiation in which the bacteroid becomes polyploid and elongated, exhibits enhanced permeability, and is no longer viable when removed from this context. In this form, the bacteroid fixes nitrogen under microaerophilic conditions. The structure of NCR247, which contains two disulfide bonds, is shown. Abbreviations: IRLC, inverted repeat–lacking clade; NCR, nodule-specific cysteine-rich.

Figure 3

Model for Staphylococcus aureus–Pseudomonas aeruginosa coinfections in cystic fibrosis patients. (a) S. aureus is a pioneer colonizer and evades the immune response with aureusimine-mediated synthesis of SSL3 and other mechanisms. (b,c) The host immune response is further challenged with production of SpA and lactate, which together aid in P. aeruginosa cocolonization. (d,e) Once established, P. aeruginosa attacks both host cells and S. aureus with an array of virulence factors, including pyocyanin, pyoverdine, pyochelin, HQNO, and PQS. (e, f ) HQNO and siderophores like pyochelin are largely responsible for P. aeruginosa’s ability to outcompete S. aureus, despite the ability of the latter to partially disarm HQNO via conversion to HQNO-OH.