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Xantholipin and several related polycyclic xanthone antibiotics feature a unique xanthone ring nucleus within a highly oxygenated, angular, fused hexacyclic system. In this study, we demonstrated that a flavin-dependent monooxygenase (FMO) XanO4 catalyzes the oxidative transformation of an anthraquinone to a xanthone system during the biosynthesis of xantholipin. In vitro isotopic labeling experiments showed that the reaction involves sequential insertion of two oxygen atoms, accompanied by an unexpected cryptic demethoxylation reaction. Moreover, characterizations of homologous FMOs of XanO4 suggested the generality of the XanO4-like-mediated reaction for the assembly of a xanthone ring in the biosynthesis of polycyclic xanthone antibiotics. These findings not only expand the repertoire of FMO activities but also reveal a novel mechanism for xanthone ring formation.

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It is reported that a wide range of bacterial infections are polymicrobial, and the members in a local microcommunity can influence the growth of neighbors through physical and chemical interactions. Pseudomonas aeruginosa is an important opportunistic pathogen that normally causes a variety of acute and chronic infections, and clinical evidences suggest that P. aeruginosa can be frequently coisolated with other pathogens from the patients with chronic infections. However, the interspecific interaction and the coexisting mechanism of P. aeruginosa with coinfecting bacterial species during evolution still remain largely unclear. In this study, the relationships of P. aeruginosa with other Gram-positive (Staphylococcus aureus) and Gram-negative (Klebsiella pneumoniae) are investigated by using a series of on-plate proximity assay, in vitro coevolution assay, and RNA-sequencing. We find that although the development of a quorum-sensing system contributes P. aeruginosa a significant growth advantage to compete with S. aureus and K. pneumoniae, the quorum-sensing regulation of P. aeruginosa will be decreased during evolution and thus provides a basis for the formation of interspecific coexistence. The results of comparative transcriptomic analyses suggest that the persistent survival of S. aureus in the microcommunity has no significant effect on the intracellular transcriptional pattern of P. aeruginosa, while a more detailed competition happens between P. aeruginosa and K. pneumoniae. Specifically, the population of P. aeruginosa with decreased quorum-sensing regulation can still restrict the proportion increase of K. pneumoniae by enhancing the type VI secretion system-elicited cell aggressivity during further coevolution. These findings provide a general explanation for the formation of a dynamic stable microcommunity consisting of more than two bacterial species, and may contribute to the development of population biology and clinical therapy.

BackgroundMicrobial communities are susceptible to the public goods dilemma, whereby individuals can gain an advantage within a group by utilizing, but not sharing the cost of producing, public goods. In bacteria, the development of quorum sensing (QS) can establish a cooperation system in a population by coordinating the production of costly and sharable extracellular products (public goods). Cooperators with intact QS system and robust ability in producing public goods are vulnerable to being undermined by QS-deficient defectors that escape from QS but benefit from the cooperation of others. Although microorganisms have evolved several mechanisms to resist cheating invasion in the public goods game, it is not clear why cooperators frequently coexist with defectors and how they form a relatively stable equilibrium during evolution.ResultsWe show that in Pseudomonas aeruginosa, QS-directed social cooperation can select a conditional defection strategy prior to the emergence of QS-mutant defectors, depending on resource availability. Conditional defectors represent a QS-inactive state of wild type (cooperator) individual and can invade QS-activated cooperators by adopting a cheating strategy, and then revert to cooperating when there are abundant nutrient supplies irrespective of the exploitation of QS-mutant defector. Our mathematical modeling further demonstrates that the incorporation of conditional defection strategy into the framework of iterated public goods game with sound punishment mechanism can lead to the coexistence of cooperator, conditional defector, and defector in a rock-paper-scissors dynamics.ConclusionsThese findings highlight the importance of behavioral heterogeneity in stabilizing the population structure and provide a potential reasonable explanation for the maintenance and evolution of cooperation in microbial communities.Electronic supplementary materialThe online version of this article (10.1186/s12915-019-0639-3) contains supplementary material, which is available to authorized users.