Quinolones: from antibiotics to autoinducers. FEMS Microbiol Rev

School of Molecular Medical Sciences, Centre for Biomolecular Sciences, University Park, University of Nottingham, Nottingham, UK.
FEMS microbiology reviews (Impact Factor: 13.24). 03/2011; 35(2):247-74. DOI: 10.1111/j.1574-6976.2010.00247.x
Source: PubMed


Since quinine was first isolated, animals, plants and microorganisms producing a wide variety of quinolone compounds have been discovered, several of which possess medicinally interesting properties ranging from antiallergenic and anticancer to antimicrobial activities. Over the years, these have served in the development of many synthetic drugs, including the successful fluoroquinolone antibiotics. Pseudomonas aeruginosa and related bacteria produce a number of 2-alkyl-4(1H)-quinolones, some of which exhibit antimicrobial activity. However, quinolones such as the Pseudomonas quinolone signal and 2-heptyl-4-hydroxyquinoline act as quorum-sensing signal molecules, controlling the expression of many virulence genes as a function of cell population density. Here, we review selectively this extensive family of bicyclic compounds, from natural and synthetic antimicrobials to signalling molecules, with a special emphasis on the biology of P. aeruginosa. In particular, we review their nomenclature and biochemistry, their multiple properties as membrane-interacting compounds, inhibitors of the cytochrome bc(1) complex and iron chelators, as well as the regulation of their biosynthesis and their integration into the intricate quorum-sensing regulatory networks governing virulence and secondary metabolite gene expression.

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    • "Furthermore, Cardozo's group recently reported that an extracellular compound of Pseudomonas inhibits methicillin-resistant Staphylococcus aureus (MRSA)[7]. Interestingly, this naturally occurring quinolone molecule also acts as a quorum-sensing (QS) signal molecule, controlling the expression of several virulence genes as a function of cell population density[4,8]. The metabolomics approach has been recently used to classify metabolites based on metabolite-profiling studies, allowing rapid analyses of complex data and the identification of novel compounds[9,10]. "

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    • "Important for P. aeruginosa pathogenesis is the hierarchical QS system, which is mediated by two chemically distinct classes of signaling molecules, the N-acylhomoserine lactones and the HAQ molecules (Pearson et al., 1997; Heeb et al., 2011). More than 50 HAQ molecules divided into five distinct series (the series A–E congeners) have been identified from P. aeruginosa, where especially the signaling molecule 3,4-dihydroxy-2-heptylquinoline (PQS; the most prominent Series B congener) is important for regulating the production of virulence factors (Deziel et al., 2004; Heeb et al., 2011). However, within bacterial populations associated with long-term infections, loci encoding the QS system have been found to accumulate mutations, and can result in extensive metabolic and phenotypic modifications of host-adapted strains compared with strains of environmental origin (Smith et al., 2006; D'Argenio et al., 2007; Yang et al., 2011; Damkiaer et al., 2013), which may subsequently affect their interaction with other microorganisms. "
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    ABSTRACT: The effect of polymicrobial interactions on pathogen physiology and how it can act either to limit pathogen colonization or to potentiate pathogen expansion and virulence are not well understood. Pseudomonas aeruginosa and Staphylococcus aureus are opportunistic pathogens commonly found together in polymicrobial human infections. However, we have previously shown that the interactions between these two bacterial species are strain dependent. Whereas P. aeruginosa PAO1, a commonly used laboratory strain, effectively suppressed S. aureus growth, we observed a commensal-like interaction between the human host-adapted strain, DK2-P2M24-2003, and S. aureus. In this study, characterization by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) imaging mass spectrometry (IMS) and mass spectral (MS) molecular networking revealed a significant metabolic divergence between P. aeruginosa PAO1 and DK2-P2M24-2003, which comprised several virulence factors and signaling 4-hydroxy-2-alkylquinoline (HAQ) molecules. Strikingly, a further modulation of the HAQ profile was observed in DK2-P2M24-2003 during interaction with S. aureus, resulting in an area with thickened colony morphology at the P. aeruginosa-S. aureus interface. In addition, we found an HAQ-mediated protection of S. aureus by DK2-P2M24-2003 from the killing effect of tobramycin. Our findings suggest a model where the metabolic divergence manifested in human host-adapted P. aeruginosa is further modulated during interaction with S. aureus and facilitate a proto-cooperative P. aeruginosa-S. aureus relationship.
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    • "Pseudomonas aeruginosa is traditionally regarded as the principle pathogen of CF disease and is one of the most common bacteria cultured from CF patients (Harrison, 2007). This bacterium is known to produce a myriad of small molecules that damage both host and microbial cells (Allen et al., 2005; Irie et al., 2005; Zulianello et al., 2006; Rada et al., 2008; Heeb et al., 2011). Rhamnolipids (Zulianello et al., 2006), phenazines (Allen et al., 2005) and quinolones (Calfee et al., 2001) have been shown to be important for the pathogenesis of this bacterium in vitro, but their role in CF disease is less well known. "
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    ABSTRACT: Cystic fibrosis (CF) lungs are filled with thick mucus that obstructs airways and facilitates chronic infections. Pseudomonas aeruginosa is a significant pathogen of this disease that produces a variety of toxic small molecules. We used molecular networking-based metabolomics to investigate the chemistry of CF sputa and assess how the microbial molecules detected reflect the microbiome and clinical culture history of the patients. Metabolites detected included xenobiotics, P. aeruginosa specialized metabolites and host sphingolipids. The clinical culture and microbiome profiles did not correspond to the detection of P. aeruginosa metabolites in the same samples. The P. aeruginosa molecules that were detected in sputum did not match those from laboratory cultures. The pseudomonas quinolone signal (PQS) was readily detectable from cultured strains, but absent from sputum, even when its precursor molecules were present. The lack of PQS production in vivo is potentially due to the chemical nature of the CF lung environment, indicating that culture-based studies of this pathogen may not explain its behavior in the lung. The most differentially abundant molecules between CF and non-CF sputum were sphingolipids, including sphingomyelins, ceramides and lactosylceramide. As these highly abundant molecules contain the inflammatory mediator ceramide, they may have a significant role in CF hyperinflammation. This study demonstrates that the chemical makeup of CF sputum is a complex milieu of microbial, host and xenobiotic molecules. Detection of a bacterium by clinical culturing and 16S rRNA gene profiling do not necessarily reflect the active production of metabolites from that bacterium in a sputum sample.
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