Endogenous Nitric Oxide Protects Bacteria Against a Wide Spectrum of Antibiotics

Gusarov, Ivan; Shatalin, Konstantin; Starodubtseva, Marina; Nudler, Evgeny

doi:10.1126/science.1175439

Cited by 358 publications

(330 citation statements)

References 26 publications

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“…Finally, at high levels NO may directly react with antibiotic compounds leading to their inactivation [113]. Therefore the effectiveness of toxic levels of NO to kill biofilms may be strongly dependent on the bacterial species and infection conditions and may elicit undesirable secondary effects that could compromise clearance of the infection.…”

Section: At Higher Levels No May Be Effective At Killing Biofilmsmentioning

confidence: 99%

Nitric Oxide: A Key Mediator of Biofilm Dispersal with Applications in Infectious Diseases

Barraud¹,

Kelso²,

Rice

et al. 2014

CPD

215

196

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Studies of the biofilm life cycle can identify novel targets and strategies for improving biofilm control measures. Of particular interest are dispersal events, where a subpopulation of cells is released from the biofilm community to search out and colonize new surfaces. Recently, the simple gas and ubiquitous biological signaling molecule nitric oxide (NO) was identified as a key mediator of biofilm dispersal conserved across microbial species. Here, we review the role and mechanisms of NO mediating dispersal in bacterial biofilms, and its potential for novel therapeutics. In contrast to previous attempts using high dose NO aimed at killing pathogens, the use of low, non-toxic NO signals (picomolar to nanomolar range) to disperse biofilms represents an innovative and highly favourable approach to improve infectious disease treatments. Further, several NO-based technologies have been developed that offer a versatile range of solutions to control biofilms, including: (i) NO-generating compounds with short or long half-lives and safe or inert residues, (ii) novel compounds for the targeted delivery of NO to infectious biofilms during systemic treatments, and (iii) novel NO-releasing materials and surface coatings for the prevention and dispersal of biofilms. Overall the use of low levels of NO exploiting its signaling properties to induce dispersal represents an unprecedented and promising strategy for the control of biofilms in clinical and industrial contexts. AbstractStudies of the biofilm life cycle can identify novel targets and strategies for improving biofilm control measures. Of particular interest are dispersal events, where a subpopulation of cells is released from the biofilm community to search out and colonize new surfaces. Recently, the simple gas and ubiquitous biological signaling molecule nitric oxide (NO) was identified as a key mediator of biofilm dispersal conserved across microbial species. Here, we review the role and mechanisms of NO mediating dispersal in bacterial biofilms, and its potential for novel therapeutics. In contrast to previous attempts using high dose NO aimed at killing pathogens, the use of low, non-toxic NO signals (picomolar to nanomolar range) to disperse biofilms represents an innovative and highly favourable approach to improve infectious disease treatments. Further, several NO-based technologies have been developed that offer a versatile range of solutions to control biofilms, including: (i) NO-generating compounds with short or long half-lives and safe or inert residues, (ii) novel compounds for the targeted delivery of NO to infectious biofilms during systemic treatments, and (iii) novel NO-releasing materials and surface coatings for the prevention and dispersal of biofilms. Overall the use of low levels of NO exploiting its signaling properties to induce dispersal represents an unprecedented and promising strategy for the control of biofilms in clinical and industrial contexts. 3 Increased antimicrobial tolerance in biofilms is the basis for chronic infecti...

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Section: At Higher Levels No May Be Effective At Killing Biofilmsmentioning

confidence: 99%

Nitric Oxide: A Key Mediator of Biofilm Dispersal with Applications in Infectious Diseases

Barraud¹,

Kelso²,

Rice

et al. 2014

CPD

215

196

View full text Add to dashboard Cite

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“…Tolerance to antibiotics may therefore depend on the ability of the cell to defend itself against ROS, as suggested by several recent studies (28)(29)(30). For example, the coordinated stringent response to nutrient limitation in P. aeruginosa and E. coli was shown to increase antioxidant enzyme expression and decrease production of prooxidant molecules, resulting in antibiotic tolerance (28).…”

mentioning

confidence: 97%

“…For example, the coordinated stringent response to nutrient limitation in P. aeruginosa and E. coli was shown to increase antioxidant enzyme expression and decrease production of prooxidant molecules, resulting in antibiotic tolerance (28). Bacteria also produce nitric oxide (NO) as well as hydrogen sulfide (H 2 S), both of which result in antibiotic tolerance via suppression of the Fenton reaction as well as increased antioxidant enzyme expression in both Gram-positive and Gramnegative bacteria (29,30).…”

mentioning

confidence: 99%

Eradication of bacterial persisters with antibiotic-generated hydroxyl radicals

Grant

Kaufmann²,

Chand³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

225

211

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During Mycobacterium tuberculosis infection, a population of bacteria likely becomes refractory to antibiotic killing in the absence of genotypic resistance, making treatment challenging. We describe an in vitro model capable of yielding a phenotypically antibiotic-tolerant subpopulation of cells, often called persisters, within populations of Mycobacterium smegmatis and M. tuberculosis . We find that persisters are distinct from the larger antibiotic-susceptible population, as a small drop in dissolved oxygen (DO) saturation (20%) allows for their survival in the face of bactericidal antibiotics. In contrast, if high levels of DO are maintained, all cells succumb, sterilizing the culture. With increasing evidence that bactericidal antibiotics induce cell death through the production of reactive oxygen species (ROS), we hypothesized that the drop in DO decreases the concentration of ROS, thereby facilitating persister survival, and maintenance of high DO yields sufficient ROS to kill persisters. Consistent with this hypothesis, the hydroxyl-radical scavenger thiourea, when added to M. smegmatis cultures maintained at high DO levels, rescues the persister population. Conversely, the antibiotic clofazimine, which increases ROS via an NADH-dependent redox cycling pathway, successfully eradicates the persister population. Recent work suggests that environmentally induced antibiotic tolerance of bulk populations may result from enhanced antioxidant capabilities. We now show that the small persister subpopulation within a larger antibiotic-susceptible population also shows differential susceptibility to antibiotic-induced hydroxyl radicals. Furthermore, we show that stimulating ROS production can eradicate persisters, thus providing a potential strategy to managing persistent infections.

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“…Bacterial NO synthases or nitrate reductases are sources of RNS that can contribute to antibiotic resistance (11,12) and increase virulence (13). Some commensal bacteria exploit host iNOS during colonic inflammation by using iNOS-derived nitrate (NO 3 − ) as a terminal electron acceptor (14).…”

mentioning

confidence: 99%

Nitrite produced byMycobacterium tuberculosisin human macrophages in physiologic oxygen impacts bacterial ATP consumption and gene expression

Cunningham‐Bussel¹,

Zhang

Nathan³

2013

Proc. Natl. Acad. Sci. U.S.A.

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In high enough concentrations, such as produced by inducible nitric oxide synthase (iNOS), reactive nitrogen species (RNS) can kill Mycobacterium tuberculosis (Mtb). Lesional macrophages in macaques and humans with tuberculosis express iNOS, and mice need iNOS to avoid succumbing rapidly to tuberculosis. However, Mtb's own ability to produce RNS is rarely considered, perhaps because nitrate reduction to nitrite is only prominent in axenic Mtb cultures at oxygen tensions ≤1%. Here we found that cultures of Mtbinfected human macrophages cultured at physiologic oxygen tensions produced copious nitrite. Surprisingly, the nitrite arose from the Mtb, not the macrophages. Mtb responded to nitrite by ceasing growth; elevating levels of ATP through reduced consumption; and altering the expression of 120 genes associated with adaptation to acid, hypoxia, nitric oxide, oxidative stress, and iron deprivation. The transcriptomic effect of endogenous nitrite was distinct from that of nitric oxide. Thus, whether or not Mtb is hypoxic, the host expresses iNOS, or hypoxia impairs the action of iNOS, Mtb in vivo is likely to encounter RNS by producing nitrite. Endogenous nitrite may slow Mtb's growth and prepare it to resist host stresses while the pathogen waits for immunopathology to promote its transmission.

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Endogenous Nitric Oxide Protects Bacteria Against a Wide Spectrum of Antibiotics

Cited by 358 publications

References 26 publications

Nitric Oxide: A Key Mediator of Biofilm Dispersal with Applications in Infectious Diseases

Nitric Oxide: A Key Mediator of Biofilm Dispersal with Applications in Infectious Diseases

Eradication of bacterial persisters with antibiotic-generated hydroxyl radicals

Nitrite produced byMycobacterium tuberculosisin human macrophages in physiologic oxygen impacts bacterial ATP consumption and gene expression

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