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Polyketide synthase function is a determinant of bacterial persistence and antibiotic tolerance in Burkholderia thailandensis

ABSTRACT: Persister cells are genetically identical variants in a bacterial population that have phenotypically modified their physiology to survive environmental stress. . To better define general persistence mechanisms that can be targeted to develop anti-persistence therapeutics, we performed transcriptomics analyses of Burkholderia thailandensis enriched for persisters using three methods: flow sorting by low proton motive force, meropenem treatment, and culture aging. Although the three persister populations generally expressed divergent gene expression profiles that underscores the multi-mechanistic nature of persistence, there were several common gene pathways expressed in two or more persister populations, including polyketide and non-ribosomal peptide synthesis, Clp proteases, mobile elements, enzymes involved in the lipid metabolism, and ATP-binding cassette (ABC) transporter systems. In particular, identification of genes that encode for polyketide synthases (PKS) and fatty acid catabolism indicate that generation of secondary metabolites, natural products, and complex lipids are needed for the maintenance of the persistence state. Persisters are markedly reduced in transposon mutants of the PKS gene BTH_I2366. Furthermore, treatment of multiple bacterial pathogens with the fatty acid synthesis inhibitor, CP-640186, potentiated antibiotic efficacy against the persisters. All together, our results suggest that bacterial persisters may exhibit an outward dormant physiology, but maintain active metabolic processes that are required to maintain persistence.

ORGANISM(S): Burkholderia thailandensis

PROVIDER: GSE127838 | GEO | 2019/03/06

REPOSITORIES: GEO

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Polyketide synthase-derived sphingolipids determine microbiota-mediated protection against pathogens inC. elegans

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2023-10-14 | GSE245296 | GEO

Expression profile for overproduction of DosP

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2014-09-15 | E-GEOD-47427 | biostudies-arrayexpress

Expression profile for overproduction of DosP

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Medium chain unsaturated fatty acid ethyl esters inhibit persister formation of Escherichia coli via antitoxin HipB

Project description:Persisters represent a small bacterial population that is dormant and that survives under antibiotic treatment without experiencing genetic adaptation. Persisters are also considered one of the major reasons for recalcitrant chronic bacterial infections. Although several mechanisms of persister formation have been proposed, it is not clear how cells enter the dormant state in the presence of antibiotics or how persister cell formation can be effectively controlled. A fatty acid compound, cis-2-decenoic acid, was reported to decrease persister formation as well as revert the dormant cells to a metabolically active state. We reasoned that some fatty acid compounds may be effective in controlling bacterial persistence because they are known to benefit host immune systems. This study investigated persister cell formation by pathogens that were exposed to nine fatty acid compounds during antibiotic treatment. We found that three medium chain unsaturated fatty acid ethyl esters (ethyl trans-2-decenoate, ethyl trans-2-octenoate, and ethyl cis-4-decenoate) decreased the level of Escherichia coli persister formation up to 110-fold when cells were exposed to ciprofloxacin or ampicillin antibiotics. RNA sequencing analysis and gene deletion persister studies elucidated that these fatty acids inhibit bacterial persistence by regulating antitoxin HipB. A similar persister cell reduction was observed for pathogenic E. coli EDL933, Pseudomonas aeruginosa PAO1, and Serratia marcescens ICU2-4 strains. This study demonstrates that fatty acid ethyl esters can be used to disrupt bacterial dormancy to combat persistent infectious diseases.

2018-08-08 | GSE112545 | GEO

Bacterial persistence - Bacterial persistence is an active σS stress response to metabolic flux limitation

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2016-09-27 | PXD001968 | Pride

Fungicide-tolerant persister formation during cryptococcal pulmonary infection

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2024-01-08 | GSE233619 | GEO

Polyketide synthase function is a determinant of bacterial persistence and antibiotic tolerance in Burkholderia thailandensis

Project description:Polyketide synthase function is a determinant of bacterial persistence and antibiotic tolerance in Burkholderia thailandensis

| PRJNA525635 | ENA

Maximizing Heterologous Expression of Engineered Type I Polyketide Synthases: Investigating Codon Optimization Strategies

Project description:Type I polyketide synthases (T1PKSs) hold an enormous potential as a rational production platform for the biosynthesis of speciality chemicals. However, despite the great progress in this field, the heterologous expression of PKSs remains a major challenge. One of the first measures to improve heterologous gene expression can be codon optimization. Although controversial, choosing the wrong codon optimization strategy can have detrimental effects on protein and product levels. In this study, we analyzed 11 different codon variants of an engineered T1PKS and investigated in a systematic approach their influence on heterologous expression in Corynebacterium glutamicum, Escherichia coli, and Pseudomonas putida. Our best performing codon variants exhibited a minimum 50-fold increase in PKS protein levels, which also enables the production of an unnatural polyketide in each of the hosts. Furthermore, we developed a free online tool (https://basebuddy.lbl.gov) that offers transparent and highly customizable codon optimization with up-to-date codon usage tables. Here, we not only highlight the significance of codon optimization but also establish the groundwork for high-throughput assembly and characterization of PKS pathways in alternative hosts.

2023-09-01 | PXD042749 | Pride

E. coli BW25113 K-12 hfq vs. wild-type persister

Project description:Persisters are cells which evade stresses like antibiotics and which are characterized by reduced metabolism and a lack of genetic alterations required to achieve this state. We showed previously that MqsR and MqsA of Escherichia coli are a toxin-antitoxin pair that influence cell physiology (e.g., biofilm formation and motility) via RNase activity as well as through regulation of toxin CspD. Here, we show that deletion of the mqsRA locus decreases persister cell formation and, consistent with this result, overexpression of MqsR increases persister cell formation. Furthermore, toxins Hha, CspD, and HokA increase persister cell formation. In addition, by overproducing MqsR in a series of isogenic mutants, we show that Hha and CspD are necessary for persister cell formation via MqsR overexpression. Surprisingly, Hfq, a small RNA chaperone, decreases persistence. A whole-transcriptome study shows that Hfq induces transport-related genes (oppA, oppB, oppC, oppD, oppF, and dppA), outer membrane protein-related genes (ybfM and ybfN), toxins (hha), and proteases (clpX, clpP, and lon). Taken together, these results indicate that toxins CspD and Hha influence persister cell formation via MqsR and that Hfq plays an important role in the regulation of persister cell formation via regulation of transport or outer membrane proteins. Strains: E. coli BW25113 K-12 hfq deleted mutant vs. wild-type Medium: LB Culture: Planktonic cell grown OD=0.5, adjusted OD=1.0, and then exposed to 100 ug/mL ampicillin for 2 h.

2009-11-07 | E-GEOD-18852 | biostudies-arrayexpress

Mapping the biosynthetic pathway of a hybrid polyketide-nonribosomal peptide in a metazoan

Project description:Polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) hybrid systems typically use complex protein-protein interactions to facilitate direct transfer of intermediates between these multimodular megaenzymes. In the canal-associated neurons (CANs) of Caenorhabditis elegans, PKS-1 and NRPS-1 produce the nemamides, the only known hybrid polyketide-nonribosomal peptides biosynthesized by animals, through a poorly understood mechanism. Here, we use genome editing and mass spectrometry to map the roles of individual PKS-1 and NRPS-1 enzymatic domains in nemamide biosynthesis. Furthermore, we show that nemamide biosynthesis requires at least five additional enzymes expressed in the CANs that are encoded by genes distributed across the worm genome. We identify the roles of these enzymes and discover a mechanism for trafficking intermediates between a PKS and an NRPS. Specifically, the enzyme PKAL-1 activates an advanced polyketide intermediate as an adenylate and directly loads it onto a carrier protein in NRPS-1. This trafficking mechanism provides a means by which a PKS-NRPS system can expand its biosynthetic potential and is likely important for the regulation of nemamide biosynthesis.

2021-06-22 | MTBLS2313 | MetaboLights

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