In the face of growing antimicrobial resistance, there is an urgent need for the development of effective strategies to target Pseudomonas aeruginosa. This metabolically versatile bacterium can cause ...a wide range of severe opportunistic infections in patients with serious underlying medical conditions, such as those with burns, surgical wounds or people with cystic fibrosis. Many of the key adaptations that arise in this organism during infection are centered on core metabolism and virulence factor synthesis. Interfering with these processes may provide a new strategy to combat infection which could be combined with conventional antibiotics. This review will provide an overview of the most recent work that has advanced our understanding of P. aeruginosa infection. Strategies that exploit this recent knowledge to combat infection will be highlighted alongside potential alternative therapeutic options and their limitations.
Display omitted
•Pseudomonas aeruginosa is a prominent gram-negative human pathogen that can thrive in a variety of challenging infection sites. Comprehending this remarkable feat is central to developing strategies to combat infection.•Many of the adaptations that occur in Pseudomonas aeruginosa during infection compared to standard laboratory conditions are centered on core metabolism. These pathways may be a key target in the fight against bacterial infection.•Pseudomonas aeruginosa infects and disseminates within hosts using a multitude of virulence factors. Targeting the synthesis of virulence factors by an antivirulence strategy represents a promising tactic for antibiotic combination therapy.
The Glyoxylate Shunt, 60 Years On Dolan, Stephen K; Welch, Martin
Annual review of microbiology,
09/2018, Volume:
72, Issue:
1
Journal Article
Peer reviewed
2017 marks the 60th anniversary of Krebs' seminal paper on the glyoxylate shunt (and coincidentally, also the 80th anniversary of his discovery of the citric acid cycle). Sixty years on, we have ...witnessed substantial developments in our understanding of how flux is partitioned between the glyoxylate shunt and the oxidative decarboxylation steps of the citric acid cycle. The last decade has shown us that the beautifully elegant textbook mechanism that regulates carbon flux through the shunt in
E. coli
is an oversimplification of the situation in many other bacteria. The aim of this review is to assess how this new knowledge is impacting our understanding of flux control at the TCA cycle glyoxylate shunt branch point in a wider range of genera, and to summarize recent findings implicating a role for the glyoxylate shunt in cellular functions other than metabolism.
Transcriptomics technologies are the techniques used to study an organism's transcriptome, the sum of all of its RNA transcripts. The information content of an organism is recorded in the DNA of its ...genome and expressed through transcription. Here, mRNA serves as a transient intermediary molecule in the information network, whilst noncoding RNAs perform additional diverse functions. A transcriptome captures a snapshot in time of the total transcripts present in a cell. The first attempts to study the whole transcriptome began in the early 1990s, and technological advances since the late 1990s have made transcriptomics a widespread discipline. Transcriptomics has been defined by repeated technological innovations that transform the field. There are two key contemporary techniques in the field: microarrays, which quantify a set of predetermined sequences, and RNA sequencing (RNA-Seq), which uses high-throughput sequencing to capture all sequences. Measuring the expression of an organism's genes in different tissues, conditions, or time points gives information on how genes are regulated and reveals details of an organism's biology. It can also help to infer the functions of previously unannotated genes. Transcriptomic analysis has enabled the study of how gene expression changes in different organisms and has been instrumental in the understanding of human disease. An analysis of gene expression in its entirety allows detection of broad coordinated trends which cannot be discerned by more targeted assays.
The Gram-negative opportunistic pathogen Pseudomonas aeruginosa is a leading cause of infections and mortality in immunocompromised patients. This organism can overcome iron deprivation during ...infection via the synthesis of two iron-chelating siderophores, pyoverdine and pyochelin, which scavenge iron from host proteins. P. aeruginosa can also uptake xenosiderophores produced by other bacteria or fungi using dedicated transporter systems. The precise substrate specificity of these siderophore transporters remains to be determined. The thiopeptide antibiotic thiostrepton exploits the pyoverdine transporters FpvA and FpvB to cross the outer membrane and reach intracellular targets. Using a series of intricate biochemical experiments, a recent study by Chan and Burrows capitalized on the specificity of thiostrepton to uncover that FpvB transports the xenosiderophores ferrichrome and ferrioxamine B with higher affinity than pyoverdine. This surprising result highlights an alternative uptake pathway for these siderophores and has significant implications for our understanding of iron acquisition in this organism.
Microbes rarely exist in isolation and instead form complex polymicrobial communities. As a result, microbes have developed intricate offensive and defensive strategies that enhance their fitness in ...these complex communities. Thus, identifying and understanding the molecular mechanisms controlling polymicrobial interactions is critical for understanding the function of microbial communities. In this study, we show that the gram-negative opportunistic human pathogen Pseudomonas aeruginosa , which frequently causes infection alongside a plethora of other microbes including fungi, encodes a genetic network which can detect and defend against gliotoxin, a potent, disulfide-containing antimicrobial produced by the ubiquitous filamentous fungus Aspergillus fumigatus . We show that gliotoxin exposure disrupts P. aeruginosa zinc homeostasis, leading to transcriptional activation of a gene encoding a previously uncharacterized dithiol oxidase (herein named as DnoP), which detoxifies gliotoxin and structurally related toxins. Despite sharing little homology to the A. fumigatus gliotoxin resistance protein (GliT), the enzymatic mechanism of DnoP from P. aeruginosa appears to be identical that used by A. fumigatus. Thus, DnoP and its transcriptional induction by low zinc represent a rare example of both convergent evolution of toxin defense and environmental cue sensing across kingdoms. Collectively, these data provide compelling evidence that P. aeruginosa has evolved to survive exposure to an A. fumigatus disulfide-containing toxin in the natural environment.
is an opportunistic human pathogen, particularly noted for causing infections in the lungs of people with cystic fibrosis (CF). Previous studies have shown that the gene expression profile of
appears ...to converge toward a common metabolic program as the organism adapts to the CF airway environment. However, we still have only a limited understanding of how these transcriptional changes impact metabolic flux at the systems level. To address this, we analyzed the transcriptome, proteome, and fluxome of
grown on glycerol or acetate. These carbon sources were chosen because they are the primary breakdown products of an airway surfactant, phosphatidylcholine, which is known to be a major carbon source for
in CF airways. We show that the fluxes of carbon throughout central metabolism are radically different among carbon sources. For example, the newly recognized "EDEMP cycle" (which incorporates elements of the Entner-Doudoroff ED pathway, the Embden-Meyerhof-Parnas EMP pathway, and the pentose phosphate PP pathway) plays an important role in supplying NADPH during growth on glycerol. In contrast, the EDEMP cycle is attenuated during growth on acetate, and instead, NADPH is primarily supplied by the reaction catalyzed by isocitrate dehydrogenase(s). Perhaps more importantly, our proteomic and transcriptomic analyses revealed a global remodeling of gene expression during growth on the different carbon sources, with unanticipated impacts on aerobic denitrification, electron transport chain architecture, and the redox economy of the cell. Collectively, these data highlight the remarkable metabolic plasticity of
; that plasticity allows the organism to seamlessly segue between different carbon sources, maximizing the energetic yield from each.
is an opportunistic human pathogen that is well known for causing infections in the airways of people with cystic fibrosis. Although it is clear that
is metabolically well adapted to life in the CF lung, little is currently known about how the organism metabolizes the nutrients available in the airways. In this work, we used a combination of gene expression and isotope tracer ("fluxomic") analyses to find out exactly where the input carbon goes during growth on two CF-relevant carbon sources, acetate and glycerol (derived from the breakdown of lung surfactant). We found that carbon is routed ("fluxed") through very different pathways during growth on these substrates and that this is accompanied by an unexpected remodeling of the cell's electron transfer pathways. Having access to this "blueprint" is important because the metabolism of
is increasingly being recognized as a target for the development of much-needed antimicrobial agents.
Highlights • Gliotoxin biosynthesis and regulation in Aspergillus fumigatus are discussed. • Gliotoxin biosynthesis requires an intact self-protection mechanism. • Altered biosynthesis or ...self-protection causes trans effects in A. fumigatus. • Gliotoxin is a very useful probe for dissecting eukaryotic biochemistry.
In this editorial, written by early-career scientists, we advocate for the invaluable role of society journals in our scientific community. By choosing to support these journals as authors, peer ...reviewers, and as editors, we can reinforce our academic growth and benefit from their re-investment back into the scientific ecosystem. Considering the numerous clear merits of this system for future generations of microbiologists and more broadly, society, we argue that early-career researchers should publish our high-quality research in society journals to shape the future of science and scientific publishing landscape.
Propionate is an abundant catabolite in nature and represents a rich potential source of carbon for the organisms that can utilize it. However, propionate and propionate-derived catabolites are also ...toxic to cells, so propionate catabolism can alternatively be viewed as a detoxification mechanism. In this review, we summarize recent progress made in understanding how prokaryotes catabolize propionic acid, how these pathways are regulated and how they might be exploited to develop novel antibacterial interventions.
The ability to switch between different lifestyles allows bacterial pathogens to thrive in diverse ecological niches
. However, a molecular understanding of their lifestyle changes within the human ...host is lacking. Here, by directly examining bacterial gene expression in human-derived samples, we discover a gene that orchestrates the transition between chronic and acute infection in the opportunistic pathogen Pseudomonas aeruginosa. The expression level of this gene, here named sicX, is the highest of the P. aeruginosa genes expressed in human chronic wound and cystic fibrosis infections, but it is expressed at extremely low levels during standard laboratory growth. We show that sicX encodes a small RNA that is strongly induced by low-oxygen conditions and post-transcriptionally regulates anaerobic ubiquinone biosynthesis. Deletion of sicX causes P. aeruginosa to switch from a chronic to an acute lifestyle in multiple mammalian models of infection. Notably, sicX is also a biomarker for this chronic-to-acute transition, as it is the most downregulated gene when a chronic infection is dispersed to cause acute septicaemia. This work solves a decades-old question regarding the molecular basis underlying the chronic-to-acute switch in P. aeruginosa and suggests oxygen as a primary environmental driver of acute lethality.
PDF
