Verapamil Targets Membrane Energetics inMycobacterium tuberculosis

ABSTRACTMycobacterium tuberculosiskills more people than any other bacterial pathogen and is becoming increasingly untreatable due to the emergence of resistance. Verapamil, an FDA-approved calcium channel blocker, potentiates the effect of several antituberculosis (anti-TB) drugsin vitroandin vivo. This potentiation is widely attributed to inhibition of the efflux pumps ofM. tuberculosis, resulting in intrabacterial drug accumulation. Here, we confirmed and quantified verapamil's synergy with several anti-TB drugs, including bedaquiline (BDQ) and clofazimine (CFZ), but found that the effect is not due to increased intrabacterial drug accumulation. We show that, consistent with itsin vitropotentiating effects on anti-TB drugs that target or require oxidative phosphorylation, the cationic amphiphile verapamil disrupts membrane function and induces a membrane stress response similar to those seen with other membrane-active agents. We recapitulated these activitiesin vitrousing inverted mycobacterial membrane vesicles, indicating a direct effect of verapamil on membrane energetics. We observed bactericidal activity against nonreplicating “persister”M. tuberculosisthat was consistent with such a mechanism of action. In addition, we demonstrated a pharmacokinetic interaction whereby human-equivalent doses of verapamil caused a boost of rifampin exposure in mice, providing a potential explanation for the observed treatment-shortening effect of verapamil in mice receiving first-line drugs. Our findings thus elucidate the mechanistic basis for verapamil's potentiation of anti-TB drugsin vitroandin vivoand highlight a previously unrecognized role for the membrane ofM. tuberculosisas a pharmacologic target.

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Edwardsiella tarda Ivy, a Lysozyme Inhibitor That Blocks the Lytic Effect of Lysozyme and Facilitates Host Infection in a Manner That Is Dependent on the Conserved Cysteine Residue

Infection and Immunity ◽

10.1128/iai.00503-13 ◽

2013 ◽

Vol 81 (10) ◽

pp. 3527-3533 ◽

Cited By ~ 21

Author(s):

Chong Wang ◽

Yong-hua Hu ◽

Bo-guang Sun ◽

Jun Li ◽

Li Sun

Keyword(s):

Bacterial Pathogen ◽

Scophthalmus Maximus ◽

Cysteine Residue ◽

Edwardsiella Tarda ◽

Broad Host Range ◽

Content Type ◽

Lytic Effect ◽

Lysozyme Inhibitor

ABSTRACTEdwardsiella tardais a Gram-negative bacterial pathogen with a broad host range that includes fish and humans. In this study, we examined the activity and function of the lysozyme inhibitor Ivy (named IvyEt) identified in the pathogenicE. tardastrain TX01. IvyEtpossesses the Ivy signature motif CKPHDC in the form of82CQPHNC87and contains several highly conserved residues, including a tryptophan (W55). For the purpose of virulence analysis, an isogenic TX01 mutant, TXivy, was created. TXivy bears an in-frame deletion of theivyEtgene. A live infection study in a turbot (Scophthalmus maximus) model showed that, compared to TX01, TXivy exhibited attenuated overall virulence, reduced tissue dissemination and colonization capacity, an impaired ability to replicate in host macrophages, and decreased resistance against the bactericidal effect of host serum. To facilitate functional analysis, recombinant IvyEt(rIvy) and three mutant proteins, i.e., rIvyW55A, rIvyC82S, and rIvyH85D, which bear Ala, Ser, and Asp substitutions at W55, C82, and H85, respectively, were prepared.In vitrostudies showed that rIvy, rIvyW55A, and rIvyH85D were able to block the lytic effect of lysozyme on a Gram-positive bacterium, whereas rIvyC82S could not do so. Likewise, rIvy, but not rIvyC82S, inhibited the serum-facilitated killing effect of lysozyme onE. tarda.In vivoanalysis showed that rIvy, but not rIvyC82S, restored the lost pathogenicity of TXivy and enhanced the infectivity of TX01. Together these results indicate that IvyEtis a lysozyme inhibitor and a virulence factor that depends on the conserved C82 for biological activity.

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Symbiotic Relationship between Streptococcus mutans and Candida albicans Synergizes Virulence of Plaque BiofilmsIn Vivo

Infection and Immunity ◽

10.1128/iai.00087-14 ◽

2014 ◽

Vol 82 (5) ◽

pp. 1968-1981 ◽

Cited By ~ 216

Author(s):

Megan L. Falsetta ◽

Marlise I. Klein ◽

Punsiri M. Colonne ◽

Kathleen Scott-Anne ◽

Stacy Gregoire ◽

...

Keyword(s):

Candida Albicans ◽

Dental Caries ◽

Streptococcus Mutans ◽

Bacterial Pathogen ◽

Single Species ◽

Content Type ◽

3 Dimensional ◽

Biofilm Development

ABSTRACTStreptococcus mutansis often cited as the main bacterial pathogen in dental caries, particularly in early-childhood caries (ECC).S. mutansmay not act alone;Candida albicanscells are frequently detected along with heavy infection byS. mutansin plaque biofilms from ECC-affected children. It remains to be elucidated whether this association is involved in the enhancement of biofilm virulence. We showed that the ability of these organisms together to form biofilms is enhancedin vitroandin vivo. The presence ofC. albicansaugments the production of exopolysaccharides (EPS), such that cospecies biofilms accrue more biomass and harbor more viableS. mutanscells than single-species biofilms. The resulting 3-dimensional biofilm architecture displays sizeableS. mutansmicrocolonies surrounded by fungal cells, which are enmeshed in a dense EPS-rich matrix. Using a rodent model, we explored the implications of this cross-kingdom interaction for the pathogenesis of dental caries. Coinfected animals displayed higher levels of infection and microbial carriage within plaque biofilms than animals infected with either species alone. Furthermore, coinfection synergistically enhanced biofilm virulence, leading to aggressive onset of the disease with rampant carious lesions. Ourin vitrodata also revealed that glucosyltransferase-derived EPS is a key mediator of cospecies biofilm development and that coexistence withC. albicansinduces the expression of virulence genes inS. mutans(e.g.,gtfB,fabM). We also found thatCandida-derived β1,3-glucans contribute to the EPS matrix structure, while fungal mannan and β-glucan provide sites for GtfB binding and activity. Altogether, we demonstrate a novel mutualistic bacterium-fungus relationship that occurs at a clinically relevant site to amplify the severity of a ubiquitous infectious disease.

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Caspase-1 and Caspase-11 Mediate Pyroptosis, Inflammation, and Control ofBrucellaJoint Infection

Infection and Immunity ◽

10.1128/iai.00361-18 ◽

2018 ◽

Vol 86 (9) ◽

Cited By ~ 21

Author(s):

Carolyn A. Lacey ◽

William J. Mitchell ◽

Alexis S. Dadelahi ◽

Jerod A. Skyberg

Keyword(s):

Interleukin 1 ◽

Joint Infection ◽

Bacterial Pathogen ◽

Joint Inflammation ◽

Dependent Manner ◽

Content Type ◽

Caspase 1 ◽

And Control

ABSTRACTBrucellosis, caused by the intracellular bacterial pathogenBrucella, is a zoonotic disease for which arthritis is the most common focal complication in humans. Here we investigated the role of inflammasomes and their effectors, including interleukin-1 (IL-1), IL-18, and pyroptosis, on inflammation and control of infection duringBrucella-induced arthritis. Early in infection, both caspase-1 and caspase-11 were found to initiate joint inflammation and proinflammatory cytokine production. However, by 1 week postinfection, caspase-1 and caspase-11 also contributed to control ofBrucellajoint infection. Inflammasome-dependent restriction ofBrucellajoint burdens did not require AIM2 (absent in melanoma 2) or NLRP3 (NLR family, pyrin domain containing 3). IL-1R had a modest effect onBrucella-induced joint swelling, but mice lacking IL-1R were not impaired in their ability to control infection of the joint byBrucella. In contrast, IL-18 contributed to the initiation of joint swelling and control of jointBrucellainfection. Caspase1/11-dependent cell death was observedin vivo, andin vitrostudies demonstrated that both caspase-1 and caspase-11 induce pyroptosis, which limitedBrucellainfection in macrophages.Brucellalipopolysaccharide alone was also able to induce caspase-11-dependent pyroptosis. Collectively, these data demonstrate that inflammasomes induce inflammation in an IL-18-dependent manner and that inflammasome-dependent IL-18 and pyroptosis restrictBrucellainfection.

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Combining the FtsZ-Targeting Prodrug TXA709 and the Cephalosporin Cefdinir Confers Synergy and Reduces the Frequency of Resistance in Methicillin-Resistant Staphylococcus aureus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00613-16 ◽

2016 ◽

Vol 60 (7) ◽

pp. 4290-4296 ◽

Cited By ~ 24

Author(s):

Malvika Kaul ◽

Lilly Mark ◽

Ajit K. Parhi ◽

Edmond J. LaVoie ◽

Daniel S. Pilch

Keyword(s):

Staphylococcus Aureus ◽

Bacterial Infections ◽

Drug Dose ◽

Drug Induced ◽

Methicillin Resistant ◽

Content Type ◽

Vancomycin Resistant ◽

Emergence Of Resistance

ABSTRACTCombination therapy of bacterial infections with synergistic drug partners offers distinct advantages over monotherapy. Among these advantages are (i) a reduction of the drug dose required for efficacy, (ii) a reduced potential for drug-induced toxicity, and (iii) a reduced potential for the emergence of resistance. Here, we describe the synergistic actions of the third-generation oral cephalosporin cefdinir and TXA709, a new, FtsZ-targeting prodrug that we have developed with improved pharmacokinetics and enhancedin vivoefficacy against methicillin-resistantStaphylococcus aureus(MRSA) relative to earlier agents. We show that the active product of TXA709 (TXA707) acts synergistically with cefdinirin vitroagainst clinical isolates of MRSA, vancomycin-intermediateS. aureus(VISA), vancomycin-resistantS. aureus(VRSA), and linezolid-resistantS. aureus(LRSA). In addition, relative to TXA707 alone, the combination of TXA707 and cefdinir significantly reduces or eliminates the detectable emergence of resistance. We also demonstrate synergyin vivowith oral administration of the prodrug TXA709 and cefdinir in mouse models of both systemic and tissue (thigh) infections with MRSA. This synergy reduces the dose of TXA709 required for efficacy 3-fold. Viewed as a whole, our results highlight the potential of TXA709 and cefdinir as a promising combination for the treatment of drug-resistant staphylococcal infections.

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Phosphatidylinositol-(3,4,5)-Trisphosphate Induces Phagocytosis of NonmotilePseudomonas aeruginosa

Infection and Immunity ◽

10.1128/iai.00215-18 ◽

2018 ◽

Vol 86 (8) ◽

Cited By ~ 5

Author(s):

Sally Demirdjian ◽

Daniel Hopkins ◽

Hector Sanchez ◽

Michael Libre ◽

Scott A. Gerber ◽

...

Keyword(s):

Pathogenic Bacteria ◽

Bacterial Pathogen ◽

Human Neutrophils ◽

Resistant Bacteria ◽

Flagellar Motility ◽

Chronic Infections ◽

Gram Negative ◽

Content Type

ABSTRACTPathogenic bacteria that establish chronic infections in immunocompromised patients frequently undergo adaptation or selection for traits that are advantageous for their growth and survival. Clinical isolates ofPseudomonas aeruginosa, a Gram-negative, opportunistic bacterial pathogen, exhibit a temporal transition from a motile to a nonmotile phenotype through loss of flagellar motility during the course of chronic infection. This progressive loss of motility is associated with increased resistance to both antibiotic and immune clearance. We have previously shown that loss of bacterial motility enablesP. aeruginosato evade phagocytic clearance bothin vitroandin vivoand fails to activate the phosphatidylinositol 3-kinase (PI3K)/Akt-dependent phagocytic pathway. Therefore, we tested the hypothesis that clearance of phagocytosis-resistant bacteria could be induced by exogenously pretreating innate immune cells with the Akt-activating molecule phosphatidylinositol-(3,4,5)-trisphosphate (PIP3). Here, we demonstrate that PIP3induces the uptake of nonmotileP. aeruginosaby primary human neutrophils >25-fold, and this effect is phenocopied with the use of murine phagocytes. However, surprisingly, mechanistic studies revealed that the induction of phagocytosis by PIP3occurs because polyphosphoinositides promote bacterial binding by the phagocytes rather than bypassing the requirement for PI3K. Moreover, this induction was selective since the uptake of other nonmotile Gram-negative, but not Gram-positive, bacteria can also be induced by PIP3. Since there is currently no treatment that effectively eradicates chronicP. aeruginosainfections, these findings provide novel insights into a potential methodology by which to induce clearance of nonmotile pathogenic bacteria and into the endogenous determinants of phagocytic recognition ofP. aeruginosa.

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Polyamines alter intestinal glucose transport

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1995.268.3.g416 ◽

1995 ◽

Vol 268 (3) ◽

pp. G416-G423 ◽

Cited By ~ 1

Author(s):

L. R. Johnson ◽

P. D. Brockway ◽

K. Madsen ◽

J. A. Hardin ◽

D. G. Gall

Keyword(s):

Glucose Transport ◽

Intestinal Transport ◽

Membrane Vesicles ◽

Membrane Lipid ◽

Membrane Function ◽

Polyamine Synthesis ◽

Primary Activity

Polyamines are required for the growth of all eukaryotic cells. Enterocytes respond to luminal nutrients with large increases in polyamine synthesis, even though they are mature, nonproliferating cells. The role of polyamines in these cells is unknown. The current experiments examined whether polyamines affected intestinal transport of glucose, since absorption is the primary activity of enterocytes and since polyamines are known to affect membrane function and stability. Glucose transport was examined in rabbit brush-border membrane vesicles (BBMV). BBMV from rabbits given 5% alpha-difluoromethylornithine (DFMO) in their drinking water 24 h before they were killed transported significantly less glucose than control vesicles [38% decrease in maximal transport rate (Jmax)]. Orogastric administration of spermine, spermidine, or putrescine to DFMO-treated animals 24 h before they were killed prevented the decrease. In rabbits receiving only orogastric spermine, glucose transport was significantly increased (64% increase in Jmax), whereas in vivo spermidine and putrescine decreased Jmax. This increase in Jmax caused by in vivo administration of spermine was not dependent on protein synthesis. Addition of polyamines whether in vivo or in vitro decreased Michaelis constant in vesicles from control and DFMO-treated animals. The change in glucose transport induced by DFMO or polyamines was not related to altered membrane lipid composition or fluidity.(ABSTRACT TRUNCATED AT 250 WORDS)

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Characterization and Vaccine Potential of Membrane Vesicles Produced by Francisella noatunensis subsp. orientalis in an Adult Zebrafish Model

Clinical and Vaccine Immunology ◽

10.1128/cvi.00557-16 ◽

2017 ◽

Vol 24 (5) ◽

Cited By ~ 15

Author(s):

Leidy Lagos ◽

Julia I. Tandberg ◽

Urska Repnik ◽

Preben Boysen ◽

Erik Ropstad ◽

...

Keyword(s):

Vaccine Development ◽

Lethal Dose ◽

Membrane Vesicles ◽

High Morbidity ◽

Zebrafish Model ◽

Content Type ◽

Spherical Structures ◽

Immunogenic Properties

ABSTRACT Vaccine development against extracellular bacteria has been important for the sustainability of the aquaculture industry. In contrast, infections with intracellular pathogens remain largely an unresolved problem. Francisella noatunensis subsp. orientalis is a Gram-negative, facultative intracellular bacterium that causes the disease francisellosis in fish. Francisellosis is commonly characterized as a chronic granulomatous disease with high morbidity and can result in high mortality depending on the host. In this study, we explored the potential of bacterial membrane vesicles (MVs) as a vaccine agent against F. noatunensis subsp. orientalis. Bacterial MVs are spherical structures naturally released from the membrane of bacteria and are often enriched with selected bacterial components such as toxins and signaling molecules. MVs were isolated from broth-cultured F. noatunensis subsp. orientalis in the present work, and proteomic analysis by mass spectrometry revealed that MVs contained a variety of immunogenic factors, including the intracellular growth proteins IglC and IglB, known to be part of a Francisella pathogenicity island (FPI), as well as outer membrane protein OmpA, chaperonin GroEL, and chaperone ClpB. By using flow cytometry and electron microscopy, we observed that F. noatunensis subsp. orientalis mainly infects myelomonocytic cells, both in vivo and in vitro. Immunization with MVs isolated from F. noatunensis subsp. orientalis protects zebrafish from subsequent challenge with a lethal dose of F. noatunensis subsp. orientalis. To determine if MVs induce a typical acute inflammatory response, mRNA expression levels were assessed by quantitative real-time PCR. Expression of tnfa, il1b, and ifng, as well as mhcii, mpeg1.1, and ighm, was upregulated, thus confirming the immunogenic properties of F. noatunensis subsp. orientalis-derived MVs.

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Uptake and Metabolism of Antibiotics Roseoflavin and 8-Demethyl-8-Aminoriboflavin in Riboflavin-Auxotrophic Listeria monocytogenes

Journal of Bacteriology ◽

10.1128/jb.00388-16 ◽

2016 ◽

Vol 198 (23) ◽

pp. 3233-3243 ◽

Cited By ~ 19

Author(s):

Andreas Matern ◽

Danielle Pedrolli ◽

Stephanie Großhennig ◽

Jörgen Johansson ◽

Matthias Mack

Keyword(s):

Listeria Monocytogenes ◽

Bacterial Pathogen ◽

Antibiotic Activity ◽

Flavin Mononucleotide ◽

Vitamin B ◽

Content Type ◽

Riboflavin Transport ◽

Uptake And Metabolism

ABSTRACTThe riboflavin analogs roseoflavin (RoF) and 8-demethyl-8-aminoriboflavin (AF) are produced by the bacteriaStreptomyces davawensisandStreptomyces cinnabarinus. Riboflavin analogs have the potential to be used as broad-spectrum antibiotics, and we therefore studied the metabolism of riboflavin (vitamin B2), RoF, and AF in the human pathogenListeria monocytogenes, a bacterium which is a riboflavin auxotroph. We show that theL. monocytogenesprotein Lmo1945 is responsible for the uptake of riboflavin, RoF, and AF. Following import, these flavins are phosphorylated/adenylylated by the bifunctional flavokinase/flavin adenine dinucleotide (FAD) synthetase Lmo1329 and adenylylated by the unique FAD synthetase Lmo0728, the first monofunctional FAD synthetase to be described in bacteria. Lmo1329 generates the cofactors flavin mononucleotide (FMN) and FAD, whereas Lmo0728 produces FAD only. The combined activities of Lmo1329 and Lmo0728 are responsible for the intracellular formation of the toxic cofactor analogs roseoflavin mononucleotide (RoFMN), roseoflavin adenine dinucleotide (RoFAD), 8-demethyl-8-aminoriboflavin mononucleotide (AFMN), and 8-demethyl-8-aminoriboflavin adenine dinucleotide (AFAD).In vivoreporter gene assays andin vitrotranscription/translation experiments show that theL. monocytogenesFMN riboswitch Rli96, which controls expression of the riboflavin transport genelmo1945, is negatively affected by riboflavin/FMN and RoF/RoFMN but not by AF/AFMN. Treatment ofL. monocytogeneswith RoF or AF leads to drastically reduced FMN/FAD levels. We suggest that the reduced flavin cofactor levels in combination with concomitant synthesis of inactive cofactor analogs (RoFMN, RoFAD, AFMN, and AFAD) explain why RoF and AF contribute to antibiotic activity inL. monocytogenes.IMPORTANCEThe riboflavin analogs roseoflavin (RoF) and 8-demethyl-8-aminoriboflavin (AF) are small molecules which are produced byStreptomyces davawensisandStreptomyces cinnabarinus. RoF and AF were reported to have antibacterial activity, and we studied how these compounds are metabolized by the human bacterial pathogenListeria monocytogenes. We found that theL. monocytogenesprotein Lmo1945 mediates uptake of AF and RoF and that the combined activities of the enzymes Lmo1329 and Lmo0728 are responsible for the conversion of AF and RoF to toxic cofactor analogs. Comparative studies with RoF and AF (a weaker antibiotic) suggest that the reduction in FMN/FAD levels and the formation of inactive FMN/FAD analogs explain to a large extent the antibiotic activity of AF and RoF.

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Kinase Targets for Mycolic Acid Biosynthesis in Mycobacterium tuberculosis

Current Molecular Pharmacology ◽

10.2174/1874467211666181025141114 ◽

2019 ◽

Vol 12 (1) ◽

pp. 27-49 ◽

Cited By ~ 6

Author(s):

Shahinda S.R. Alsayed ◽

Chau C. Beh ◽

Neil R. Foster ◽

Alan D. Payne ◽

Yu Yu ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Enzymatic Activity ◽

Bacterial Pathogen ◽

Building Blocks ◽

Mycolic Acid ◽

Adaptive Responses ◽

Mycolic Acids ◽

Hydroxylated Fatty Acids

Background:Mycolic acids (MAs) are the characteristic, integral building blocks for the mycomembrane belonging to the insidious bacterial pathogen Mycobacterium tuberculosis (M.tb). These C60-C90 long α-alkyl-β-hydroxylated fatty acids provide protection to the tubercle bacilli against the outside threats, thus allowing its survival, virulence and resistance to the current antibacterial agents. In the post-genomic era, progress has been made towards understanding the crucial enzymatic machineries involved in the biosynthesis of MAs in M.tb. However, gaps still remain in the exact role of the phosphorylation and dephosphorylation of regulatory mechanisms within these systems. To date, a total of 11 serine-threonine protein kinases (STPKs) are found in M.tb. Most enzymes implicated in the MAs synthesis were found to be phosphorylated in vitro and/or in vivo. For instance, phosphorylation of KasA, KasB, mtFabH, InhA, MabA, and FadD32 downregulated their enzymatic activity, while phosphorylation of VirS increased its enzymatic activity. These observations suggest that the kinases and phosphatases system could play a role in M.tb adaptive responses and survival mechanisms in the human host. As the mycobacterial STPKs do not share a high sequence homology to the human’s, there have been some early drug discovery efforts towards developing potent and selective inhibitors.Objective:Recent updates to the kinases and phosphatases involved in the regulation of MAs biosynthesis will be presented in this mini-review, including their known small molecule inhibitors.Conclusion:Mycobacterial kinases and phosphatases involved in the MAs regulation may serve as a useful avenue for antitubercular therapy.

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Exogenous Alginate Protects Staphylococcus aureus from Killing by Pseudomonas aeruginosa

Journal of Bacteriology ◽

10.1128/jb.00559-19 ◽

2019 ◽

Vol 202 (8) ◽

Cited By ~ 2

Author(s):

Courtney E. Price ◽

Dustin G. Brown ◽

Dominique H. Limoli ◽

Vanessa V. Phelan ◽

George A. O’Toole

Keyword(s):

Staphylococcus Aureus ◽

Pseudomonas Aeruginosa ◽

Physical Space ◽

Late Time ◽

Protective Effects ◽

Content Type ◽

Alginate Production ◽

The Impact

ABSTRACT Cystic fibrosis (CF) patients chronically infected with both Pseudomonas aeruginosa and Staphylococcus aureus have worse health outcomes than patients who are monoinfected with either P. aeruginosa or S. aureus. We showed previously that mucoid strains of P. aeruginosa can coexist with S. aureus in vitro due to the transcriptional downregulation of several toxic exoproducts typically produced by P. aeruginosa, including siderophores, rhamnolipids, and HQNO (2-heptyl-4-hydroxyquinoline N-oxide). Here, we demonstrate that exogenous alginate protects S. aureus from P. aeruginosa in both planktonic and biofilm coculture models under a variety of nutritional conditions. S. aureus protection in the presence of exogenous alginate is due to the transcriptional downregulation of pvdA, a gene required for the production of the iron-scavenging siderophore pyoverdine as well as the downregulation of the PQS (Pseudomonas quinolone signal) (2-heptyl-3,4-dihydroxyquinoline) quorum sensing system. The impact of exogenous alginate is independent of endogenous alginate production. We further demonstrate that coculture of mucoid P. aeruginosa with nonmucoid P. aeruginosa strains can mitigate the killing of S. aureus by the nonmucoid strain of P. aeruginosa, indicating that the mechanism that we describe here may function in vivo in the context of mixed infections. Finally, we investigated a panel of mucoid clinical isolates that retain the ability to kill S. aureus at late time points and show that each strain has a unique expression profile, indicating that mucoid isolates can overcome the S. aureus-protective effects of mucoidy in a strain-specific manner. IMPORTANCE CF patients are chronically infected by polymicrobial communities. The two dominant bacterial pathogens that infect the lungs of CF patients are P. aeruginosa and S. aureus, with ∼30% of patients coinfected by both species. Such coinfected individuals have worse outcomes than monoinfected patients, and both species persist within the same physical space. A variety of host and environmental factors have been demonstrated to promote P. aeruginosa-S. aureus coexistence, despite evidence that P. aeruginosa kills S. aureus when these organisms are cocultured in vitro. Thus, a better understanding of P. aeruginosa-S. aureus interactions, particularly mechanisms by which these microorganisms are able to coexist in proximal physical space, will lead to better-informed treatments for chronic polymicrobial infections.

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