scholarly journals Vibrio cholerae VciB Mediates Iron Reduction

2017 ◽  
Vol 199 (12) ◽  
Author(s):  
Eric D. Peng ◽  
Shelley M. Payne
Keyword(s):  
Electron Transport ◽  
Vibrio Cholerae ◽  
Ferrous Iron ◽  
Electron Transport Chain ◽  
Iron Reduction ◽  
Iron Transport ◽  
Ferric Iron ◽  
Transport Systems ◽  
Content Type ◽  
Transport Chain

ABSTRACT Vibrio cholerae is the causative agent of the severe diarrheal disease cholera. V. cholerae thrives within the human host, where it replicates to high numbers, but it also persists within the aquatic environments of ocean and brackish water. To survive within these nutritionally diverse environments, V. cholerae must encode the necessary tools to acquire the essential nutrient iron in all forms it may encounter. A prior study of systems involved in iron transport in V. cholerae revealed the existence of vciB, which, while unable to directly transport iron, stimulates the transport of iron through ferrous (Fe2+) iron transport systems. We demonstrate here a role for VciB in V. cholerae in which VciB stimulates the reduction of Fe3+ to Fe2+, which can be subsequently transported into the cell with the ferrous iron transporter Feo. Iron reduction is independent of functional iron transport but is associated with the electron transport chain. Comparative analysis of VciB orthologs suggests a similar role for other proteins in the VciB family. Our data indicate that VciB is a dimer located in the inner membrane with three transmembrane segments and a large periplasmic loop. Directed mutagenesis of the protein reveals two highly conserved histidine residues required for function. Taken together, our results support a model whereby VciB reduces ferric iron using energy from the electron transport chain. IMPORTANCE Vibrio cholerae is a prolific human pathogen and environmental organism. The acquisition of essential nutrients such as iron is critical for replication, and V. cholerae encodes a number of mechanisms to use iron from diverse environments. Here, we describe the V. cholerae protein VciB that increases the reduction of oxidized ferric iron (Fe3+) to the ferrous form (Fe2+), thus promoting iron acquisition through ferrous iron transporters. Analysis of VciB orthologs in Burkholderia and Aeromonas spp. suggest that they have a similar activity, allowing a functional assignment for this previously uncharacterized protein family. This study builds upon our understanding of proteins known to mediate iron reduction in bacteria.

scholarly journals Investigation of the Electron Transport Chain to and the Catalytic Activity of the Diheme CytochromecPeroxidase CcpA of Shewanella oneidensis

2011 ◽  
Vol 77 (17) ◽  
pp. 6172-6180 ◽  
Author(s):  
Björn Schütz ◽  
Julian Seidel ◽  
Gunnar Sturm ◽  
Oliver Einsle ◽  
Johannes Gescher
Keyword(s):  
Electron Transport ◽  
Peroxidase Activity ◽  
Electron Transport Chain ◽  
Ferric Iron ◽  
Shewanella Oneidensis ◽  
Selective Advantage ◽  
Competitive Growth ◽  
Content Type ◽  
Transport Chain

ABSTRACTBacterial dihemec-type cytochrome peroxidases (BCCPs) catalyze the periplasmic reduction of hydrogen peroxide to water. The gammaproteobacteriumShewanella oneidensisproduces the peroxidase CcpA under a number of anaerobic conditions, including dissimilatory iron-reducing conditions. We wanted to understand the function of this protein in the organism and its putative connection to the electron transport chain to ferric iron. CcpA was isolated and tested for peroxidase activity, and its structural conformation was analyzed by X-ray crystallography. CcpA exhibitedin vitroperoxidase activity and had a structure typical of diheme peroxidases. It was produced in almost equal amounts under anaerobic and microaerophilic conditions. With 50 mM ferric citrate and 50 μM oxygen in the growth medium, CcpA expression results in a strong selective advantage for the cell, which was detected in competitive growth experiments with wild-type and ΔccpAmutant cells that lack the entireccpAgene due to a markerless deletion. We were unable to reduce CcpA directly with CymA, MtrA, or FccA, which are known key players in the chain of electron transport to ferric iron and fumarate but identified the small monoheme ScyA as a mediator of electron transport between CymA and BCCP. To our knowledge, this is the first detailed description of a complete chain of electron transport to a periplasmicc-type cytochrome peroxidase. This study furthermore reports the possibility of establishing a specific electron transport chain usingc-type cytochromes.

scholarly journals Physiological Evidence for Isopotential Tunneling in the Electron Transport Chain of Methane-Producing Archaea

2017 ◽  
Vol 83 (18) ◽  
Author(s):  
Nikolas Duszenko ◽  
Nicole R. Buan
Keyword(s):  
Escherichia Coli ◽  
Electron Transport ◽  
Stationary Phase ◽  
Exponential Growth ◽  
Electron Transport Chain ◽  
Methanosarcina Barkeri ◽  
Metabolic Efficiency ◽  
Methanosarcina Acetivorans ◽  
Content Type ◽  
Transport Chain

ABSTRACT Many, but not all, organisms use quinones to conserve energy in their electron transport chains. Fermentative bacteria and methane-producing archaea (methanogens) do not produce quinones but have devised other ways to generate ATP. Methanophenazine (MPh) is a unique membrane electron carrier found in Methanosarcina species that plays the same role as quinones in the electron transport chain. To extend the analogy between quinones and MPh, we compared the MPh pool sizes between two well-studied Methanosarcina species, Methanosarcina acetivorans C2A and Methanosarcina barkeri Fusaro, to the quinone pool size in the bacterium Escherichia coli. We found the quantity of MPh per cell increases as cultures transition from exponential growth to stationary phase, and absolute quantities of MPh were 3-fold higher in M. acetivorans than in M. barkeri. The concentration of MPh suggests the cell membrane of M. acetivorans, but not of M. barkeri, is electrically quantized as if it were a single conductive metal sheet and near optimal for rate of electron transport. Similarly, stationary (but not exponentially growing) E. coli cells also have electrically quantized membranes on the basis of quinone content. Consistent with our hypothesis, we demonstrated that the exogenous addition of phenazine increases the growth rate of M. barkeri three times that of M. acetivorans. Our work suggests electron flux through MPh is naturally higher in M. acetivorans than in M. barkeri and that hydrogen cycling is less efficient at conserving energy than scalar proton translocation using MPh. IMPORTANCE Can we grow more from less? The ability to optimize and manipulate metabolic efficiency in cells is the difference between commercially viable and nonviable renewable technologies. Much can be learned from methane-producing archaea (methanogens) which evolved a successful metabolic lifestyle under extreme thermodynamic constraints. Methanogens use highly efficient electron transport systems and supramolecular complexes to optimize electron and carbon flow to control biomass synthesis and the production of methane. Worldwide, methanogens are used to generate renewable methane for heat, electricity, and transportation. Our observations suggest Methanosarcina acetivorans, but not Methanosarcina barkeri, has electrically quantized membranes. Escherichia coli, a model facultative anaerobe, has optimal electron transport at the stationary phase but not during exponential growth. This study also suggests the metabolic efficiency of bacteria and archaea can be improved using exogenously supplied lipophilic electron carriers. The enhancement of methanogen electron transport through methanophenazine has the potential to increase renewable methane production at an industrial scale.

scholarly journals Secreted Pyomelanin of Legionella pneumophila Promotes Bacterial Iron Uptake and Growth under Iron-Limiting Conditions

2013 ◽  
Vol 81 (11) ◽  
pp. 4182-4191 ◽  
Author(s):  
Huaixin Zheng ◽  
Christa H. Chatfield ◽  
Mark R. Liles ◽  
Nicholas P. Cianciotto
Keyword(s):  
Legionella Pneumophila ◽  
Ferrous Iron ◽  
Iron Uptake ◽  
Iron Transport ◽  
Ferric Iron ◽  
Iron Acquisition ◽  
Ferric Hydroxide ◽  
Supernatant Fraction ◽  
Content Type ◽  
Ferrous Iron Transport

ABSTRACTIron acquisition is critical to the growth and virulence ofLegionella pneumophila. Previously, we found thatL. pneumophilauses both a ferrisiderophore pathway and ferrous iron transport to obtain iron. We now report that two molecules secreted byL. pneumophila, homogentisic acid (HGA) and its polymerized variant (HGA-melanin, a pyomelanin), are able to directly mediate the reduction of various ferric iron salts. Furthermore, HGA, synthetic HGA-melanin, and HGA-melanin derived from bacterial supernatants enhanced the ability ofL. pneumophilaand other species ofLegionellato take up radiolabeled iron. Enhanced iron uptake was not observed with a ferrous iron transport mutant. Thus, HGA and HGA-melanin mediate ferric iron reduction, with the resulting ferrous iron being available to the bacterium for uptake. Upon further testing ofL. pneumophilaculture supernatants, we found that significant amounts of ferric and ferrous iron were associated with secreted HGA-melanin. Importantly, a pyomelanin-containing fraction obtained from a wild-type culture supernatant was able to stimulate the growth of iron-starved legionellae. That the corresponding supernatant fraction obtained from a nonpigmented mutant culture did not stimulate growth demonstrated that HGA-melanin is able to both promote iron uptake and enhance growth under iron-limiting conditions. Indicative of a complementary role in iron acquisition, HGA-melanin levels were inversely related to the levels of siderophore activity. Compatible with a role in the ecology and pathogenesis ofL. pneumophila, HGA and HGA-melanin were effective at reducing and releasing iron from both insoluble ferric hydroxide and the mammalian iron chelates ferritin and transferrin.

scholarly journals Vibrio cholerae FeoA, FeoB, and FeoC Interact To Form a Complex

2016 ◽  
Vol 198 (7) ◽  
pp. 1160-1170 ◽  
Author(s):  
Begoña Stevenson ◽  
Elizabeth E. Wyckoff ◽  
Shelley M. Payne
Keyword(s):  
Complex Formation ◽  
Vibrio Cholerae ◽  
Ferrous Iron ◽  
Iron Transport ◽  
Active Form ◽  
Integral Membrane Protein ◽  
Content Type ◽  
Membrane Complex ◽  
Ferrous Iron Transport

ABSTRACTFeo is the major ferrous iron transport system in prokaryotes. Despite having been discovered over 25 years ago and found to be widely distributed among bacteria, Feo is poorly understood, as its structure and mechanism of iron transport have not been determined. Thefeooperon inVibrio choleraeis made up of three genes, encoding the FeoA, FeoB, and FeoC proteins, which are all required for Feo system function. FeoA and FeoC are both small cytoplasmic proteins, and their function remains unclear. FeoB, which is thought to function as a ferrous iron permease, is a large integral membrane protein made up of an N-terminal GTPase domain and a C-terminal membrane-spanning region. To date, structural studies of FeoB have been carried out using a truncated form of the protein encompassing only the N-terminal GTPase region. In this report, we show that full-length FeoB forms higher-order complexes when cross-linkedin vivoinV. cholerae. Our analysis of these complexes revealed that FeoB can simultaneously associate with both FeoA and FeoC to form a large complex, an observation that has not been reported previously. We demonstrate that interactions between FeoB and FeoA, but not between FeoB and FeoC, are required for complex formation. Additionally, we identify amino acid residues in the GTPase region of FeoB that are required for function of the Feo system and for complex formation. These observations suggest that this large Feo complex may be the active form of Feo that is used for ferrous iron transport.IMPORTANCEThe Feo system is the major route for ferrous iron transport in bacteria. In this work, theVibrio choleraeFeo proteins, FeoA, FeoB, and FeoC, are shown to interact to form a large inner membrane complexin vivo. This is the first report showing an interaction among all three Feo proteins. It is also determined that FeoA, but not FeoC, is required for Feo complex assembly.

scholarly journals Genomic, Proteomic, and Biochemical Analysis of the Organohalide Respiratory Pathway in Desulfitobacterium dehalogenans

2014 ◽  
Vol 197 (5) ◽  
pp. 893-904 ◽  
Author(s):  
Thomas Kruse ◽  
Bram A. van de Pas ◽  
Ariane Atteia ◽  
Klaas Krab ◽  
Wilfred R. Hagen ◽  
...  
Keyword(s):  
Electron Transport ◽  
Electron Acceptor ◽  
Electron Transport Chain ◽  
Biochemical Analysis ◽  
Active Components ◽  
Organohalide Respiration ◽  
Content Type ◽  
Membrane Complex ◽  
Redox Active ◽  
Transport Chain

Desulfitobacterium dehalogenansis able to grow by organohalide respiration using 3-chloro-4-hydroxyphenyl acetate (Cl-OHPA) as an electron acceptor. We used a combination of genome sequencing, biochemical analysis of redox active components, and shotgun proteomics to study elements of the organohalide respiratory electron transport chain. The genome ofDesulfitobacterium dehalogenansJW/IU-DC1Tconsists of a single circular chromosome of 4,321,753 bp with a GC content of 44.97%. The genome contains 4,252 genes, including six rRNA operons and six predicted reductive dehalogenases. One of the reductive dehalogenases, CprA, is encoded by a well-characterizedcprTKZEBACDgene cluster. Redox active components were identified in concentrated suspensions of cells grown on formate and Cl-OHPA or formate and fumarate, using electron paramagnetic resonance (EPR), visible spectroscopy, and high-performance liquid chromatography (HPLC) analysis of membrane extracts. In cell suspensions, these components were reduced upon addition of formate and oxidized after addition of Cl-OHPA, indicating involvement in organohalide respiration. Genome analysis revealed genes that likely encode the identified components of the electron transport chain from formate to fumarate or Cl-OHPA. Data presented here suggest that the first part of the electron transport chain from formate to fumarate or Cl-OHPA is shared. Electrons are channeled from an outward-facing formate dehydrogenase via menaquinones to a fumarate reductase located at the cytoplasmic face of the membrane. When Cl-OHPA is the terminal electron acceptor, electrons are transferred from menaquinones to outward-facing CprA, via an as-yet-unidentified membrane complex, and potentially an extracellular flavoprotein acting as an electron shuttle between the quinol dehydrogenase membrane complex and CprA.

scholarly journals Insights into the Fundamental Physiology of the Uncultured Fe-Oxidizing BacteriumLeptothrix ochracea

2018 ◽  
Vol 84 (9) ◽  
Author(s):  
E. J. Fleming ◽  
T. Woyke ◽  
R. A. Donatello ◽  
M. M. M. Kuypers ◽  
A. Sczyrba ◽  
...  
Keyword(s):  
Electron Transport ◽  
Single Cell ◽  
Electron Transport Chain ◽  
Natural Waters ◽  
Iron Oxidation ◽  
Complex Iii ◽  
Total Carbon ◽  
Bisphosphate Carboxylase ◽  
Content Type ◽  
Transport Chain

ABSTRACTLeptothrix ochraceais known for producing large volumes of iron oxyhydroxide sheaths that alter wetland biogeochemistry. For over a century, these delicate structures have fascinated microbiologists and geoscientists. BecauseL. ochraceastill resists long-termin vitroculture, the debate regarding its metabolic classification dates back to 1885. We developed a novel culturing technique forL. ochraceausingin situnatural waters and coupled this with single-cell genomics and nanoscale secondary-ion mass spectrophotometry (nanoSIMS) to probeL. ochracea's physiology. In microslide culturesL. ochraceadoubled every 5.7 h and had an absolute growth requirement for ferrous iron, the genomic capacity for iron oxidation, and a branched electron transport chain with cytochromes putatively involved in lithotrophic iron oxidation. Additionally, its genome encoded several electron transport chain proteins, including a molybdopterin alternative complex III (ACIII), a cytochromebdoxidase reductase, and several terminal oxidase genes.L. ochraceacontained two key autotrophic proteins in the Calvin-Benson-Bassham cycle, a form II ribulose bisphosphate carboxylase, and a phosphoribulose kinase.L. ochraceaalso assimilated bicarbonate, although calculations suggest that bicarbonate assimilation is a small fraction of its total carbon assimilation. Finally,L. ochracea's fundamental physiology is a hybrid of those of the chemolithotrophicGallionella-type iron-oxidizing bacteria and the sheathed, heterotrophic filamentous metal-oxidizing bacteria of theLeptothrix-Sphaerotilusgenera. This allowsL. ochraceato inhabit a unique niche within the neutrophilic iron seeps.IMPORTANCELeptothrix ochraceawas one of three groups of organisms that Sergei Winogradsky used in the 1880s to develop his hypothesis on chemolithotrophy.L. ochraceacontinues to resist cultivation and appears to have an absolute requirement for organic-rich waters, suggesting that its true physiology remains unknown. Further,L. ochraceais an ecological engineer; a fewL. ochraceacells can generate prodigious volumes of iron oxyhydroxides, changing the ecosystem's geochemistry and ecology. Therefore, to determineL. ochracea's basic physiology, we employed new single-cell techniques to demonstrate thatL. ochraceaoxidizes iron to generate energy and, despite having predicted genes for autotrophic growth, assimilates a fraction of the total CO2that autotrophs do. Although not a true chemolithoautotroph,L. ochracea's physiological strategy allows it to be flexible and to extensively colonize iron-rich wetlands.

scholarly journals Neutralization of Mitochondrial Superoxide by Superoxide Dismutase 2 Promotes Bacterial Clearance and Regulates Phagocyte Numbers in Zebrafish

2014 ◽  
Vol 83 (1) ◽  
pp. 430-440 ◽  
Author(s):  
E. M. Peterman ◽  
C. Sullivan ◽  
M. F. Goody ◽  
I. Rodriguez-Nunez ◽  
J. A. Yoder ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Electron Transport ◽  
Mitochondrial Dysfunction ◽  
Electron Transport Chain ◽  
Bacterial Burden ◽  
Content Type ◽  
Mitochondrial Ros ◽  
Transport Chain ◽  
Severe Infections ◽  
Superoxide Dismutase 2

Mitochondria are known primarily as the location of the electron transport chain and energy production in cells. More recently, mitochondria have been shown to be signaling centers for apoptosis and inflammation. Reactive oxygen species (ROS) generated as by-products of the electron transport chain within mitochondria significantly impact cellular signaling pathways. Because of the toxic nature of ROS, mitochondria possess an antioxidant enzyme, superoxide dismutase 2 (SOD2), to neutralize ROS. If mitochondrial antioxidant enzymes are overwhelmed during severe infections, mitochondrial dysfunction can occur and lead to multiorgan failure or death.Pseudomonas aeruginosais an opportunistic pathogen that can infect immunocompromised patients. Infochemicals and exotoxins associated withP. aeruginosaare capable of causing mitochondrial dysfunction. In this work, we describe the roles of SOD2 and mitochondrial ROS regulation in the zebrafish innate immune response toP. aeruginosainfection.sod2is upregulated in mammalian macrophages and neutrophils in response to lipopolysaccharidein vitro, andsod2knockdown in zebrafish results in an increased bacterial burden. Further investigation revealed that phagocyte numbers are compromised in Sod2-deficient zebrafish. Addition of the mitochondrion-targeted ROS-scavenging chemical MitoTEMPO rescues neutrophil numbers and reduces the bacterial burden in Sod2-deficient zebrafish. Our work highlights the importance of mitochondrial ROS regulation by SOD2 in the context of innate immunity and supports the use of mitochondrion-targeted ROS scavengers as potential adjuvant therapies during severe infections.

scholarly journals Nitric Oxide Protects Bacteria from Aminoglycosides by Blocking the Energy-Dependent Phases of Drug Uptake

2011 ◽  
Vol 55 (5) ◽  
pp. 2189-2196 ◽  
Author(s):  
Bruce D. McCollister ◽  
Matthew Hoffman ◽  
Maroof Husain ◽  
Andrés Vázquez-Torres
Keyword(s):  
Nitric Oxide ◽  
Electron Transport ◽  
Electron Transport Chain ◽  
Respiratory Activity ◽  
Inflammatory Responses ◽  
Drug Uptake ◽  
No Donor ◽  
Content Type ◽  
Transport Chain ◽  
Energy Dependent

ABSTRACTOur investigations have identified a mechanism by which exogenous production of nitric oxide (NO) induces resistance of Gram-positive and -negative bacteria to aminoglycosides. An NO donor was found to protectSalmonellaspp. against structurally diverse classes of aminoglycosides of the 4,6-disubstituted 2-deoxystreptamine group. Likewise, NO generated enzymatically by inducible NO synthase of gamma interferon-primed macrophages protected intracellularSalmonellaagainst the cytotoxicity of gentamicin. NO levels that elicited protection against aminoglycosides repressedSalmonellarespiratory activity. NO nitrosylated terminal quinol cytochrome oxidases, without exerting long-lasting inhibition of NADH dehydrogenases of the electron transport chain. The NO-mediated repression of respiratory activity blocked both energy-dependent phases I and II of aminoglycoside uptake but not the initial electrostatic interaction of the drug with the bacterial cell envelope. As seen inSalmonella, the NO-dependent inhibition of the electron transport chain also afforded aminoglycoside resistance to the clinically important pathogensPseudomonas aeruginosaandStaphylococcus aureus. Together, these findings provide evidence for a model in which repression of aerobic respiration by NO fluxes associated with host inflammatory responses can reduce drug uptake, thus promoting resistance to several members of the aminoglycoside family in phylogenetically diverse bacteria.

scholarly journals Staphylococcus epidermidis SrrAB Regulates Bacterial Growth and Biofilm Formation Differently under Oxic and Microaerobic Conditions

2014 ◽  
Vol 197 (3) ◽  
pp. 459-476 ◽  
Author(s):  
Youcong Wu ◽  
Yang Wu ◽  
Tao Zhu ◽  
Haiyan Han ◽  
Huayong Liu ◽  
...  
Keyword(s):  
Electron Transport ◽  
Staphylococcus Epidermidis ◽  
Biofilm Formation ◽  
Electron Transport Chain ◽  
Regulatory Function ◽  
Dependent Manner ◽  
Mobility Shift ◽  
Content Type ◽  
Transport Chain ◽  
Microaerobic Conditions

SrrAB expression inStaphylococcus epidermidisstrain 1457 (SE1457) was upregulated during a shift from oxic to microaerobic conditions. AnsrrAdeletion (ΔsrrA) mutant was constructed for studying the regulatory function of SrrAB. The deletion resulted in retarded growth and abolished biofilm formation bothin vitroandin vivoand under both oxic and microaerobic conditions. Associated with the reduced biofilm formation, the ΔsrrAmutant produced much less polysaccharide intercellular adhesion (PIA) and showed decreased initial adherence capacity. Microarray analysis showed that thesrrAmutation affected transcription of 230 genes under microaerobic conditions, and 51 genes under oxic conditions. Quantitative real-time PCR confirmed this observation and showed downregulation of genes involved in maintaining the electron transport chain by supporting cytochrome and quinol-oxidase assembly (e.g.,qoxBandctaA) and in anaerobic metabolism (e.g.,pflBAandnrdD). In the ΔsrrAmutant, the expression of the biofilm formation-related geneicaRwas upregulated under oxic conditions and downregulated under microaerobic conditions, whereasicaAwas downregulated under both conditions. An electrophoretic mobility shift assay further revealed that phosphorylated SrrA bound to the promoter regions oficaR,icaA,qoxB, andpflBA, as well as its own promoter region. These findings demonstrate that inS. epidermidisSrrAB is an autoregulator and regulates biofilm formation in anica-dependent manner. Under oxic conditions, SrrAB modulates electron transport chain activity by positively regulatingqoxBACDtranscription. Under microaerobic conditions, it regulates fermentation processes and DNA synthesis by modulating the expression of both thepfloperon andnrdDG.

scholarly journals Novel MenA Inhibitors Are Bactericidal againstMycobacterium tuberculosisand Synergize with Electron Transport Chain Inhibitors

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Bryan J. Berube ◽  
Dara Russell ◽  
Lina Castro ◽  
Seoung-ryoung Choi ◽  
Prabagaran Narayanasamy ◽  
...  
Keyword(s):  
Electron Transport ◽  
Drug Treatment ◽  
Electron Transport Chain ◽  
Drug Targets ◽  
Content Type ◽  
Atp Production ◽  
Highly Active ◽  
Enhanced Activity ◽  
Transport Chain ◽  
Long Course

ABSTRACTMycobacterium tuberculosisis the leading cause of morbidity and death resulting from infectious disease worldwide. The incredible disease burden, combined with the long course of drug treatment and an increasing incidence of antimicrobial resistance amongM. tuberculosisisolates, necessitates novel drugs and drug targets for treatment of this deadly pathogen. Recent work has produced several promising clinical candidates targeting components of the electron transport chain (ETC) ofM. tuberculosis, highlighting this pathway’s potential as a drug target. Menaquinone is an essential component of theM. tuberculosisETC, as it functions to shuttle electrons through the ETC to produce the electrochemical gradient required for ATP production for the cell. We show that inhibitors of MenA, a component of the menaquinone biosynthetic pathway, are highly active againstM. tuberculosis. MenA inhibitors are bactericidal againstM. tuberculosisunder both replicating and nonreplicating conditions, with 10-fold higher bactericidal activity against nutrient-starved bacteria than against replicating cultures. MenA inhibitors have enhanced activity in combination with bedaquiline, clofazimine, and inhibitors of QcrB, a component of the cytochromebc1oxidase. Together, these data support MenA as a viable target for drug treatment againstM. tuberculosis. MenA inhibitors not only killM. tuberculosisin a variety of physiological states but also show enhanced activity in combination with ETC inhibitors in various stages of clinical trial testing.

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