The Fatty Acid Signaling Molecule
            <i>cis</i>
            -2-Decenoic Acid Increases Metabolic Activity and Reverts Persister Cells to an Antimicrobial-Susceptible State

Marques, Cláudia N. H.; Morozov, Aleksey; Planzos, Penny; Zelaya, Hector M.

doi:10.1128/aem.01576-14

Cited by 122 publications

(131 citation statements)

References 103 publications

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“…In general, polyP plays pivotal roles in various stress-related networks in bacteria (73), and it is conceivable that interactions between polyP and RNA polymerase (74) and/or ribosomes (75) are causative for the observed phenotypes of S. aureus pitA6 strains. Accordingly, a fatty acid signaling molecule that was shown to render bacterial persisters more drug sensitive favors enzymatic degradation of polyP (76).…”

Section: Discussionmentioning

confidence: 99%

A Novel Point Mutation Promotes Growth Phase-Dependent Daptomycin Tolerance in Staphylococcus aureus

Mechler

Herbig

Paprotka

et al. 2015

Antimicrob Agents Chemother

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Recalcitrance of genetically susceptible bacteria to antibiotic killing is a hallmark of bacterial drug tolerance. This phenomenon is prevalent in biofilms, persisters, and also planktonic cells and is associated with chronic or relapsing infections with pathogens such as Staphylococcus aureus. Here we report the in vitro evolution of an S. aureus strain that exhibits a high degree of nonsusceptibility to daptomycin as a result of cyclic challenges with bactericidal concentrations of the drug. This phenotype was attributed to stationary growth phase-dependent drug tolerance and was clearly distinguished from resistance. The underlying genetic basis was revealed to be an adaptive point mutation in the putative inorganic phosphate (P i ) transporter gene pitA. Drug tolerance caused by this allele, termed pitA6, was abrogated when the upstream gene pitR was inactivated. Enhanced tolerance toward daptomycin, as well as the acyldepsipeptide antibiotic ADEP4 and various combinations of other drugs, was accompanied by elevated intracellular concentrations of P i and polyphosphate, which may reversibly interfere with critical cellular functions. The evolved strain displayed increased rates of survival within human endothelial cells, demonstrating the correlation of intracellular persistence and drug tolerance. These findings will be useful for further investigations of S. aureus drug tolerance, toward the development of additional antipersister compounds and strategies.

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Section: Discussionmentioning

confidence: 99%

A Novel Point Mutation Promotes Growth Phase-Dependent Daptomycin Tolerance in Staphylococcus aureus

Mechler

Herbig

Paprotka

et al. 2015

Antimicrob Agents Chemother

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“…Recently, the hipAB system of Shewanella oneidensis was characterized, and a ternary HipAB-DNA complex different from the one from E. coli was observed (46). Since persister cells are highly problematic with respect to antibiotic treatments of infectious diseases, much emphasis has been placed on the development of drugs that suppress the development and survival of persister cells (47)(48)(49)(50)(51)(52)(53).…”

Section: Persister Cells As a Classical Model For Phenotypic Heterogementioning

confidence: 99%

Phenotypic Heterogeneity, a Phenomenon That May Explain Why Quorum Sensing Does Not Always Result in Truly Homogenous Cell Behavior

Grote

Krysciak

Streit

2015

Appl Environ Microbiol

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Phenotypic heterogeneity describes the occurrence of "nonconformist" cells within an isogenic population. The nonconformists show an expression profile partially different from that of the remainder of the population. Phenotypic heterogeneity affects many aspects of the different bacterial lifestyles, and it is assumed that it increases bacterial fitness and the chances for survival of the whole population or smaller subpopulations in unfavorable environments. Well-known examples for phenotypic heterogeneity have been associated with antibiotic resistance and frequently occurring persister cells. Other examples include heterogeneous behavior within biofilms, DNA uptake and bacterial competence, motility (i.e., the synthesis of additional flagella), onset of spore formation, lysis of phages within a small subpopulation, and others. Interestingly, phenotypic heterogeneity was recently also observed with respect to quorum-sensing (QS)-dependent processes, and the expression of autoinducer (AI) synthase genes and other QS-dependent genes was found to be highly heterogeneous at a single-cell level. This phenomenon was observed in several Gram-negative bacteria affiliated with the genera Vibrio, Dinoroseobacter, Pseudomonas, Sinorhizobium, and Mesorhizobium. A similar observation was made for the Gram-positive bacterium Listeria monocytogenes. Since AI molecules have historically been thought to be the keys to homogeneous behavior within isogenic populations, the observation of heterogeneous expression is quite intriguing and adds a new level of complexity to the QS-dependent regulatory networks. All together, the many examples of phenotypic heterogeneity imply that we may have to partially revise the concept of homogeneous and coordinated gene expression in isogenic bacterial populations. Bacteria have evolved multiple strategies to cope with rapid and frequent changes in their environment. These survival strategies may include spore formation, increased production of polysaccharides, biofilm formation or escape from biofilms (i.e., switching from a motile into a sessile form and vice versa), altered motility, change of metabolic capabilities, response to antibiotics, and many more. In general, these switches are initiated by environmental or bacterially produced signals that are perceived by a diverse array of regulators and delegated into the corresponding regulatory networks. This presumably results in altered transcription levels of different genes or operons, which eventually causes a change in the phenotype and a response to the environmental stimulus. Within this context, it is generally assumed that the majority of a population will undergo this switch within a short time period and that the population will show a mostly homogeneous expression profile. During the last decade, it became, however, evident that a certain fraction of cells in an isogenic population behaves differently from the others, even though the environment may not have changed significantly. The term "phenotypic heterogeneity" thereby descr...

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“…cis-2-Decenoic acid increased the respiratory activity caused by changes in protein abundances. As a consequence these cells became more sensitive against antibiotics and the number of surviving cells decreases in biofilm treated with such a combined therapy [69]. When methicillin-resistant Staphylococcus aureus (MRSA) were exposed to 125 μg mL -1 cis-2-decenoic acid the formation of biofilms and at >500 μg mL -1 growth was inhibited.…”

Section: Prevention and Dispersal Of Biofilms Using Cis-2-alkenoic Acmentioning

confidence: 99%

cis-2-Alkenoic Acids as Promising Drugs for the Control of Biofilm Infections

Yuyama¹,

Abraham

2016

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Microbes attached to surfaces and form biofilms where they are difficult to eradicate. Here they are embedded in a complex matrix of polymers and are much less sensitive against antibiotics or the immune system. This is a growing problem, especially for implants; hence, novel approaches are urgently needed to control biofilm infections. Many of these approaches interfere with the communication between the microbial cells required for biofilm formation and maintenance, a process known as quorum sensing. But microbes have also several mechanisms to disperse their own biofilms if conditions become unfavourable. Recently, it has been found that the pathogen Pseudomonas aeruginosa disperses its mature biofilms using cis-2-decenoic acid. This fatty acid belongs to a group of cis-2-alkenoic acids which are known from several bacteria and are also triggering the communication between different species. In this review the biosynthesis of these compounds, their signal transduction and their role in species-species communication are presented. Examples are discussed where cis-2-alkenoic acids have been used to eradicate biofilms and enhance the sensitivity of pathogens against antibiotics, either alone or in combination with antibiotics. Although this presents an interesting approach for the control of biofilm infections it is still in its infancy and a much broader characterization of the effects of cis-2-alkenoic acids are needed before moving to any medical application.Keywords: biofilm, quorum-sensing, diffusible signal factor (DSF), quorum-quenching, host-pathogen interaction, cis-2-alkenoic acids, antibiotics 1 Pathogens organized in biofilms are difficult to eradicateMicroorganisms can attach to surfaces where they form biofilms, microbial aggregates embedded in a complex and structured matrix of polymers [1]. In human infections they are found on many implants but also on teeth [2] or the mucosa, e. g. in the cystic fibrosis lung [3], the skin [4] or the middle ear [5]. These aggregates are structurally complex, dynamic systems with a multitude of interactions between the community members and the host [6]. Biofilm formation is a key factor for the survival of microbes but biofilms have also the ability to disperse under unfavourable conditions to colonize new niches [7]. Biofilm infections cause many deaths and high health costs worldwide, e. g. in the U. S. alone 32% of all healthcare-associated infections are urinary tract infections, 22% are surgical site infections and 14% are blood stream infections causing costs between $5000 and $34,000 per infection and summing up to more than $5 billion in added medical costs per annum [8].The main problem comes not so much from the human pathogens causing the infections but from their organization in biofilms. Biofilm are formed for the protection of the cells against hostile environmental conditions. As a consequence, biofilm infections are difficult to eradicate because of much better protection against antibiotics compared to free living cells [9]. It has been...

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The Fatty Acid Signaling Molecule cis -2-Decenoic Acid Increases Metabolic Activity and Reverts Persister Cells to an Antimicrobial-Susceptible State

Cited by 122 publications

References 103 publications

A Novel Point Mutation Promotes Growth Phase-Dependent Daptomycin Tolerance in Staphylococcus aureus

A Novel Point Mutation Promotes Growth Phase-Dependent Daptomycin Tolerance in Staphylococcus aureus

Phenotypic Heterogeneity, a Phenomenon That May Explain Why Quorum Sensing Does Not Always Result in Truly Homogenous Cell Behavior

cis-2-Alkenoic Acids as Promising Drugs for the Control of Biofilm Infections

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