A Matter of Timing: Contrasting Effects of Hydrogen Sulfide on Oxidative Stress Response in Shewanella oneidensis

ABSTRACTHydrogen sulfide (H2S), well known for its toxic properties, has recently become a research focus in bacteria, in part because it has been found to prevent oxidative stress caused by treatment with some antibiotics. H2S has the ability to scavenge reactive oxygen species (ROS), thus preventing oxidative stress, but it is also toxic, leading to conflicting reports of its effects in different organisms. Here, withShewanella oneidensisas a model, we report that the effects of H2S on the response to oxidative stress are time dependent. When added simultaneously with H2O2, H2S promoted H2O2toxicity by inactivating catalase, KatB, a heme-containing enzyme involved in H2O2degradation. Such an inhibitory effect may apply to other heme-containing proteins, such as cytochromecbb3oxidase. When H2O2was supplied 20 min or later after the addition of H2S, the oxidative-stress-responding regulator OxyR was activated, resulting in increased resistance to H2O2. The activation of OxyR was likely triggered by the influx of iron, a response to lowered intracellular iron due to the iron-sequestering property of H2S. Given thatShewanellabacteria thrive in redox-stratified environments that have abundant sulfur and iron species, our results imply that H2S is more important for bacterial survival in such environmental niches than previously believed.IMPORTANCEPrevious studies have demonstrated that H2S is either detrimental or beneficial to bacterial cells. While it can act as a growth-inhibiting molecule by damaging DNA and denaturing proteins, it helps cells to combat oxidative stress. Here we report that H2S indeed has these contrasting biological functions and that its effects are time dependent. Immediately after H2S treatment, there is growth inhibition due to damage of heme-containing proteins, at least to catalase and cytochromecoxidase. In contrast, when added a certain time later, H2S confers an enhanced ability to combat oxidative stress by activating the H2O2-responding regulator OxyR. Our data reconcile conflicting observations about the functions of H2S.

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Evolution and Sequence Diversity of FhuA inSalmonellaandEscherichia

Infection and Immunity ◽

10.1128/iai.00573-18 ◽

2018 ◽

Vol 86 (11) ◽

Cited By ~ 3

Author(s):

Yejun Wang ◽

Xiongbin Chen ◽

Yueming Hu ◽

Guoqiang Zhu ◽

Aaron P. White ◽

...

Keyword(s):

Gene Mutations ◽

Comparative Sequence Analysis ◽

Sequence Diversity ◽

Bacterial Cells ◽

Bacterial Survival ◽

Bacterial Strains ◽

Content Type ◽

High Conservation ◽

High Selection ◽

Clustering Pattern

ABSTRACTThefhuACDBoperon, present in a number ofEnterobacteriaceae, encodes components essential for the uptake of ferric hydroxamate type siderophores. FhuA acts not only as a transporter for physiologically important chelated ferric iron but also as a receptor for various bacteriophages, toxins, and antibiotics, which are pathogenic to bacterial cells. In this research,fhuAgene distribution and sequence diversity were investigated inEnterobacteriaceae, especiallySalmonellaandEscherichia. Comparative sequence analysis resulted in afhuAphylogenetic tree that did not match the expected phylogeny of species or trees of thefhuCDBgenes. ThefhuAsequences showed a unique mosaic clustering pattern. On the other hand, the gene sequences showed high conservation for strains from the same serovar or serotype. In total, six clusters were identified from FhuA proteins inSalmonellaandEscherichia, among which typical peptide fragment variations could be defined. Six fragmental insertions/deletions and two substitution fragments were discovered, for which the combination of polymorphism patterns could well classify the different clusters. Structural modeling demonstrated that all the six featured insertions/deletions and one substitution fragment are located at the apexes of the long loops present as part of the FhuA external pocket. These frequently mutated regions are likely under high selection pressure, with bacterial strains balancing escape from phage infection or toxin/antibiotics attack viafhuAgene mutations while maintaining the siderophore uptake activity essential for bacterial survival. The unusualfhuAclustering suggests that high-frequency exchange offhuAgenes has occurred between enterobacterial strains after distinctive species were established.

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EseE of Edwardsiella tarda Augments Secretion of Translocon Protein EseC and Expression of theescC-eseEOperon

Infection and Immunity ◽

10.1128/iai.00106-16 ◽

2016 ◽

Vol 84 (8) ◽

pp. 2336-2344 ◽

Cited By ~ 6

Author(s):

Jia Yi ◽

Shui Bing Xiao ◽

Zhi Xiong Zeng ◽

Jin Fang Lu ◽

Lu Yi Liu ◽

...

Keyword(s):

Gel Filtration ◽

Host Cells ◽

Edwardsiella Tarda ◽

Supernatant Fraction ◽

Bacterial Cells ◽

Bacterial Survival ◽

Content Type ◽

Chaperone Protein ◽

Pulldown Assay ◽

Novel Protein

Edwardsiella tardais an important Gram-negative pathogen that employs a type III secretion system (T3SS) to deliver effectors into host cells to facilitate bacterial survival and replication. These effectors are translocated into host cells through a translocon complex composed of three secreted proteins, namely, EseB, EseC, and EseD. The secretion of EseB and EseD requires a chaperone protein called EscC, whereas the secretion of EseC requires the chaperone EscA. In this study, we identified a novel protein (EseE) that also regulates the secretion of EseC. AneseEdeletion mutant secreted much less EseC into supernatants, accompanied by increased EseC levels within bacterial cells. We also demonstrated that EseE interacted directly with EseC in a pulldown assay. Interestingly, EseC, EseE, and EscA were able to form a ternary complex, as revealed by pulldown and gel filtration assays. Of particular importance, the deletion ofeseEresulted in decreased levels of EseB and EseD proteins in both the bacterial pellet and supernatant fraction. Furthermore, real-time PCR assays showed that EseE positively regulated the transcription of the translocon operonescC-eseE, comprisingescC,eseB,escA,eseC,eseD, andeseE. These effects of EseE on the translocon components/operon appeared to have a functional consequence, since the ΔeseEstrain was outcompeted by wild-typeE. tardain a mixed infection in blue gourami fish. Collectively, our results demonstrate that EseE not only functions as a chaperone for EseC but also acts as a positive regulator controlling the expression of the translocon operonescC-eseE, thus contributing to the pathogenesis ofE. tardain fish.

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Overexpression offetA(ybbL) andfetB(ybbM), Encoding an Iron Exporter, Enhances Resistance to Oxidative Stress in Escherichia coli

Applied and Environmental Microbiology ◽

10.1128/aem.02322-13 ◽

2013 ◽

Vol 79 (23) ◽

pp. 7210-7219 ◽

Cited By ~ 20

Author(s):

Sergios A. Nicolaou ◽

Alan G. Fast ◽

Eiko Nakamaru-Ogiso ◽

Eleftherios T. Papoutsakis

Keyword(s):

Oxidative Stress ◽

Escherichia Coli ◽

Iron Overload ◽

Parent Strain ◽

Iron Homeostasis ◽

Intracellular Iron ◽

Paramagnetic Resonance ◽

Content Type ◽

Genomic Libraries ◽

Metal Transporter

ABSTRACTReactive oxygen species are generated by redox reactions and the Fenton reaction of H2O2and iron that generates the hydroxyl radical that causes severe DNA, protein, and lipid damage. We screenedEscherichia coligenomic libraries to identify a fragment, containingcueR,ybbJ,qmcA,ybbL, andybbM, which enhanced resistance to H2O2stress. We report that the ΔybbLand ΔybbMstrains are more susceptible to H2O2stress than the parent strain and thatybbLandybbMoverexpression overcomes H2O2sensitivity. TheybbLandybbMgenes are predicted to code for an ATP-binding cassette metal transporter, and we demonstrate that YbbM is a membrane protein. We investigated various metals to identify iron as the likely substrate of this transporter. We propose the gene namesfetAandfetB(for Fe transport) and the gene product names FetA and FetB. FetAB allows for increased resistance to oxidative stress in the presence of iron, revealing a role in iron homeostasis. We show that iron overload coupled with H2O2stress is abrogated byfetAandfetBoverexpression in the parent strain and in the Δfurstrain, where iron uptake is deregulated. Furthermore, we utilized whole-cell electron paramagnetic resonance to show that intracellular iron levels in the Δfurstrain are decreased by 37% byfetAandfetBoverexpression. Combined, these findings show thatfetAandfetBencode an iron exporter that has a role in enhancing resistance to H2O2-mediated oxidative stress and can minimize oxidative stress under conditions of iron overload and suggest that FetAB facilitates iron homeostasis to decrease oxidative stress.

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Manganese Detoxification by MntE Is Critical for Resistance to Oxidative Stress and Virulence of Staphylococcus aureus

mBio ◽

10.1128/mbio.02915-18 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 12

Author(s):

Caroline M. Grunenwald ◽

Jacob E. Choby ◽

Lillian J. Juttukonda ◽

William N. Beavers ◽

Andy Weiss ◽

...

Keyword(s):

Oxidative Stress ◽

Staphylococcus Aureus ◽

Pathogenic Bacteria ◽

Efflux Pump ◽

Uptake System ◽

Cation Diffusion ◽

Intracellular Iron ◽

Cation Diffusion Facilitator ◽

Mn Toxicity ◽

Content Type

ABSTRACT Manganese (Mn) is an essential micronutrient critical for the pathogenesis of Staphylococcus aureus, a significant cause of human morbidity and mortality. Paradoxically, excess Mn is toxic; therefore, maintenance of intracellular Mn homeostasis is required for survival. Here we describe a Mn exporter in S. aureus, MntE, which is a member of the cation diffusion facilitator (CDF) protein family and conserved among Gram-positive pathogens. Upregulation of mntE transcription in response to excess Mn is dependent on the presence of MntR, a transcriptional repressor of the mntABC Mn uptake system. Inactivation of mntE or mntR leads to reduced growth in media supplemented with Mn, demonstrating MntE is required for detoxification of excess Mn. Inactivation of mntE results in elevated levels of intracellular Mn, but reduced intracellular iron (Fe) levels, supporting the hypothesis that MntE functions as a Mn efflux pump and Mn efflux influences Fe homeostasis. Strains inactivated for mntE are more sensitive to the oxidants NaOCl and paraquat, indicating Mn homeostasis is critical for resisting oxidative stress. Furthermore, mntE and mntR are required for full virulence of S. aureus during infection, suggesting S. aureus experiences Mn toxicity in vivo. Combined, these data support a model in which MntR controls Mn homeostasis by balancing transcriptional repression of mntABC and induction of mntE, both of which are critical for S. aureus pathogenesis. Thus, Mn efflux contributes to bacterial survival and virulence during infection, establishing MntE as a potential antimicrobial target and expanding our understanding of Mn homeostasis. IMPORTANCE Manganese (Mn) is generally viewed as a critical nutrient that is beneficial to pathogenic bacteria due to its function as an enzymatic cofactor and its capability of acting as an antioxidant; yet paradoxically, high concentrations of this transition metal can be toxic. In this work, we demonstrate Staphylococcus aureus utilizes the cation diffusion facilitator (CDF) family protein MntE to alleviate Mn toxicity through efflux of excess Mn. Inactivation of mntE leads to a significant reduction in S. aureus resistance to oxidative stress and S. aureus-mediated mortality within a mouse model of systemic infection. These results highlight the importance of MntE-mediated Mn detoxification in intracellular Mn homeostasis, resistance to oxidative stress, and S. aureus virulence. Therefore, this establishes MntE as a potential target for development of anti-S. aureus therapeutics.

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Alkyl Hydroperoxide Reductase Is Required for Helicobacter cinaedi Intestinal Colonization and Survival under Oxidative Stress in BALB/c and BALB/c Interleukin-10−/−Mice

Infection and Immunity ◽

10.1128/iai.05477-11 ◽

2011 ◽

Vol 80 (3) ◽

pp. 921-928 ◽

Cited By ~ 20

Author(s):

Nisanart Charoenlap ◽

Zeli Shen ◽

Megan E. McBee ◽

Suresh Muthupalani ◽

Gerald N. Wogan ◽

...

Keyword(s):

Oxidative Stress ◽

Serum Levels ◽

Interleukin 10 ◽

Intestinal Bacterium ◽

Bacterial Survival ◽

Alkyl Hydroperoxide Reductase ◽

Content Type ◽

Helicobacter Cinaedi ◽

Alkyl Hydroperoxide

Helicobacter cinaedi, a common human intestinal bacterium, has been implicated in various enteric and systemic diseases in normal and immunocompromised patients. Protection against oxidative stress is a crucial component of bacterium-host interactions. Alkyl hydroperoxide reductase C (AhpC) is an enzyme responsible for detoxification of peroxides and is important in protection from peroxide-induced stress.H. cinaedipossesses a singleahpC, which was investigated with respect to its role in bacterial survival during oxidative stress. TheH. cinaedi ahpCmutant had diminished resistance to organic hydroperoxide toxicity but increased hydrogen peroxide resistance compared with the wild-type (WT) strain. The mutant also exhibited an oxygen-sensitive phenotype and was more susceptible to killing by macrophages than the WT strain.In vivoexperiments in BALB/c and BALB/c interleukin-10 (IL-10)−/−mice revealed that the cecal colonizing ability of theahpCmutant was significantly reduced. The mutant also had diminished ability to induce bacterium-specific immune responsesin vivo, as shown by immunoglobulin (IgG2a and IgG1) serum levels. Collectively, these data suggest thatH. cinaedi ahpCnot only contributes to protecting the organism against oxidative stress but also alters its pathogenic propertiesin vivo.

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IdeR, a DtxR Family Iron Response Regulator, Controls Iron Homeostasis, Morphological Differentiation, Secondary Metabolism, and the Oxidative Stress Response inStreptomyces avermitilis

Applied and Environmental Microbiology ◽

10.1128/aem.01503-18 ◽

2018 ◽

Vol 84 (22) ◽

Cited By ~ 5

Author(s):

Yaqing Cheng ◽

Renjun Yang ◽

Mengya Lyu ◽

Shiwei Wang ◽

Xingchao Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Stress Response ◽

Secondary Metabolism ◽

Iron Homeostasis ◽

Morphological Differentiation ◽

Oxidative Stress Response ◽

Regulatory Role ◽

Intracellular Iron ◽

Content Type

ABSTRACTIron, an essential element for microorganisms, functions as a vital cofactor in a wide variety of key metabolic processes. On the other hand, excess iron may have toxic effects on bacteria by catalyzing the formation of reactive oxygen species through the Fenton reaction. The prevention of iron toxicity requires the precise control of intracellular iron levels in bacteria. Mechanisms of iron homeostasis in the genusStreptomyces(the producers of various antibiotics) are poorly understood.Streptomyces avermitilisis the industrial producer of avermectins, which are potent anthelmintic agents widely used in medicine, agriculture, and animal husbandry. We investigated the regulatory role of IdeR, a DtxR family regulator, inS. avermitilis. In the presence of iron, IdeR binds to a specific palindromic consensus sequence in promoters and regulates 14 targets involved in iron metabolism (e.g., iron acquisition, iron storage, heme metabolism, and Fe-S assembly). IdeR also directly regulates 12 targets involved in other biological processes, including morphological differentiation, secondary metabolism, carbohydrate metabolism, and the tricarboxylic acid (TCA) cycle.ideRtranscription is positively regulated by the peroxide-sensing transcriptional regulator OxyR. A newly constructedideRdeletion mutant (DideR) was found to be less responsive to iron levels and more sensitive to H2O2treatment than the wild-type strain, indicating thatideRis essential for oxidative stress responses. Our findings, taken together, demonstrate that IdeR plays a pleiotropic role in the overall coordination of metabolism inStreptomycesspp. in response to iron levels.IMPORTANCEIron is essential to almost all organisms, but in the presence of oxygen, iron is both poorly available and potentially toxic.Streptomycesspecies are predominantly present in soil where the environment is complex and fluctuating. So far, the mechanism of iron homeostasis inStreptomycesspp. remains to be elucidated. Here, we characterized the regulatory role of IdeR in the avermectin-producing organismS. avermitilis. IdeR maintains intracellular iron levels by regulating genes involved in iron absorption and storage. IdeR also directly regulates morphological differentiation, secondary metabolism, and central metabolism.ideRis under the positive control of OxyR and is indispensable for an efficient response to oxidative stress. This investigation uncovered that IdeR acts as a global regulator coordinating iron homeostasis, morphological differentiation, secondary metabolism, and oxidative stress response inStreptomycesspecies. Elucidation of the pleiotropic regulation function of IdeR provides new insights into the mechanisms of howStreptomycesspp. adapt to the complex environment.

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Protective Role of Bacterial Alkanesulfonate Monooxygenase under Oxidative Stress

Applied and Environmental Microbiology ◽

10.1128/aem.00692-20 ◽

2020 ◽

Vol 86 (15) ◽

Cited By ~ 1

Author(s):

Chulwoo Park ◽

Bora Shin ◽

Woojun Park

Keyword(s):

Oxidative Stress ◽

Protective Role ◽

Sulfur Cycle ◽

Bacterial Survival ◽

Content Type ◽

Alkanesulfonate Monooxygenase ◽

Cellular Stresses ◽

Charged Ions ◽

And Oxidative Stress

ABSTRACT Bacterial alkane metabolism is associated with a number of cellular stresses, including membrane stress and oxidative stress, and the limited uptake of charged ions such as sulfate. In the present study, the genes ssuD and tauD in Acinetobacter oleivorans DR1 cells, which encode an alkanesulfonate monooxygenase and a taurine dioxygenase, respectively, were found to be responsible for hexadecanesulfonate (C16SO3H) and taurine metabolism, and Cbl was experimentally identified as a potential regulator of ssuD and tauD expression. The expression of ssuD and tauD occurred under sulfate-limited conditions generated during n-hexadecane degradation. Interestingly, expression analysis and knockout experiments suggested that both genes are required to protect cells against oxidative stress, including that generated by n-hexadecane degradation and H2O2 exposure. Measurable levels of intracellular hexadecanesulfonate were also produced during n-hexadecane degradation. Phylogenetic analysis suggested that ssuD and tauD are mainly present in soil-dwelling aerobes within the Betaproteobacteria and Gammaproteobacteria classes, which suggests that they function as controllers of the sulfur cycle and play a protective role against oxidative stress in sulfur-limited conditions. IMPORTANCE ssuD and tauD, which play a role in the degradation of organosulfonate, were expressed during n-hexadecane metabolism and oxidative stress conditions in A. oleivorans DR1. Our study confirmed that hexadecanesulfonate was accidentally generated during bacterial n-hexadecane degradation in sulfate-limited conditions. Removal of this by-product by SsuD and TauD must be necessary for bacterial survival under oxidative stress generated during n-hexadecane degradation.

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Interplay between Manganese and Iron in Pneumococcal Pathogenesis: Role of the Orphan Response Regulator RitR

Infection and Immunity ◽

10.1128/iai.00805-12 ◽

2012 ◽

Vol 81 (2) ◽

pp. 421-429 ◽

Cited By ~ 27

Author(s):

Cheryl-Lynn Y. Ong ◽

Adam J. Potter ◽

Claudia Trappetti ◽

Mark J. Walker ◽

Michael P. Jennings ◽

...

Keyword(s):

Oxidative Stress ◽

Iron Uptake ◽

Metal Ion ◽

Response Regulator ◽

Transport Systems ◽

Bacterial Cells ◽

Content Type ◽

Manganese Ion ◽

Iron And Manganese

ABSTRACTStreptococcus pneumoniae(the pneumococcus) is a major human pathogen that is carried asymptomatically in the nasopharynx by up to 70% of the human population. Translocation of the bacteria into internal sites can cause a range of diseases, such as pneumonia, otitis media, meningitis, and bacteremia. This transition from nasopharynx to growth at systemic sites means that the pneumococcus needs to adjust to a variety of environmental conditions, including transition metal ion availability. Although it is an important nutrient, iron potentiates oxidative stress, and it is established that inS. pneumoniae, expression of iron transport systems and proteins that protect against oxidative stress are regulated by an orphan response regulator, RitR. In this study, we investigated the effect of iron and manganese ion availability on the growth of aritRmutant. Deletion ofritRled to impaired growth of bacteria in high-iron medium, but this phenotype could be suppressed with the addition of manganese. Measurement of metal ion accumulation indicated that manganese prevents iron accumulation. Furthermore, the addition of manganese also led to a reduction in the amount of hydrogen peroxide produced by bacterial cells. Studies of virulence in a murine model of infection indicated that RitR was not essential for pneumococcal survival and suggested that derepression of iron uptake systems may enhance the survival of pneumococci in some niches.

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Succinic Semialdehyde Promotes Prosurvival Capability of Agrobacterium tumefaciens

Journal of Bacteriology ◽

10.1128/jb.00373-15 ◽

2016 ◽

Vol 198 (6) ◽

pp. 930-940 ◽

Cited By ~ 3

Author(s):

Chao Wang ◽

Desong Tang ◽

Yong-Gui Gao ◽

Lian-Hui Zhang

Keyword(s):

Oxidative Stress ◽

Agrobacterium Tumefaciens ◽

Plant Pathogen ◽

Biological Significance ◽

Nitrate Assimilation ◽

Quorum Quenching ◽

Succinic Semialdehyde ◽

Bacterial Survival ◽

Content Type ◽

A Genome

ABSTRACTSuccinic semialdehyde (SSA), an important metabolite of γ-aminobutyric acid (GABA), is a ligand of the repressor AttJ regulating the expression of theattJ-attKLMgene cluster in the plant pathogenAgrobacterium tumefaciens. While the response ofA. tumefaciensto GABA and the function ofattKLMhave been extensively studied, genetic and physiological responses ofA. tumefaciensto SSA remain unknown. In combination with microarray and genetic approaches, this study sets out to explore new roles of the SSA-AttJKLM regulatory mechanism during bacterial infection. The results showed that SSA plays a key role in regulation of several bacterial activities, including C4-dicarboxylate utilization, nitrate assimilation, and resistance to oxidative stress. Interestingly, while the SSA relies heavily on the functional AttKLM in mediating nitrate assimilation and oxidative stress resistance, the compound could regulate utilization of C4-dicarboxylates independent of AttJKLM. We further provide evidence that SSA controls C4-dicarboxylate utilization through induction of an SSA importer and that disruption ofattKLMattenuates the tumorigenicity ofA. tumefaciens. Taken together, these findings indicate that SSA could be a potent plant signal which, together with AttKLM, plays a vital role in promoting the bacterial prosurvival abilities during infection.IMPORTANCEAgrobacterium tumefaciensis a plant pathogen causing crown gall diseases and has been well known as a powerful tool for plant genetic engineering. During the long history of microbe-host interaction,A. tumefacienshas evolved the capabilities of recognition and response to plant-derived chemical metabolites. Succinic semialdehyde (SSA) is one such metabolite. Previous results have demonstrated that SSA functions to activate a quorum-quenching mechanism and thus to decrease the level of quorum-sensing signals, thereby avoiding the elicitation of a plant defense. Here, we studied the effect of SSA on gene expression at a genome-wide level and reported that SSA also promotes bacterial survival during infection. These findings provide a new insight on the biological significance of chemical signaling between agrobacteria and plant hosts.

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Sulfide ProtectsStaphylococcus aureusfrom Aminoglycoside Antibiotics but Cannot Be Regarded as a General Defense Mechanism against Antibiotics

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00602-18 ◽

2018 ◽

Vol 62 (10) ◽

Cited By ~ 5

Author(s):

Julia Weikum ◽

Niklas Ritzmann ◽

Nils Jelden ◽

Anna Klöckner ◽

Sebastian Herkersdorf ◽

...

Keyword(s):

Defense Mechanism ◽

Model Organism ◽

Inhibitory Effect ◽

Aminoglycoside Antibiotics ◽

Drug Uptake ◽

Protective Mechanism ◽

Bacterial Cells ◽

Content Type ◽

Sulfide Production ◽

The Impact

ABSTRACTSulfide production has been proposed to be a universal defense mechanism against antibiotics in bacteria (K. Shatalin, E. Shatalina, A. Mironov, and E. Nudler, Science 334:986–990, 2011, doi:10.1126/science.1209855). To gain insight into the mechanism underlying sulfide protection, we systematically and comparatively addressed the interference of sulfide with antibiotic activity againstStaphylococcus aureus, as a model organism. The impact of sulfide and sulfide precursors on the antibiotic susceptibility ofS. aureusto the most important classes of antibiotics was analyzed using modified disk diffusion assays, killing kinetic assays, and drug uptake studies. In addition, sulfide production and the impact of exogenously added sulfide on the physiology ofS. aureuswere analyzed. Sulfide protection was found to be limited to aminoglycoside antibiotics, which are known to be taken up by bacterial cells in an energy-dependent process. The protective mechanism was found to rely on an inhibitory effect of sulfide on the bacterial respiratory chain, leading to reduced drug uptake.S. aureuswas found to be incapable of producing substantial amounts of sulfide. We propose that bacterial sulfide production should not be regarded as a general defense mechanism against antibiotics, since (i) it is limited to aminoglycosides and (ii) production levels vary considerably among species and, as forS. aureus, may be too low for protection.

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