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22


Nitric Oxide protects Gram-positive bacteria against a wide spectrum of antimicrobials [Meeting Abstract]

Gusarov, I
ISI:000278440700059
ISSN: 1089-8603
CID: 111897

Endogenous nitric oxide protects bacteria against a wide spectrum of antibiotics

Gusarov, Ivan; Shatalin, Konstantin; Starodubtseva, Marina; Nudler, Evgeny
Bacterial nitric oxide synthases (bNOS) are present in many Gram-positive species and have been demonstrated to synthesize NO from arginine in vitro and in vivo. However, the physiological role of bNOS remains largely unknown. We show that NO generated by bNOS increases the resistance of bacteria to a broad spectrum of antibiotics, enabling the bacteria to survive and share habitats with antibiotic-producing microorganisms. NO-mediated resistance is achieved through both the chemical modification of toxic compounds and the alleviation of the oxidative stress imposed by many antibiotics. Our results suggest that the inhibition of NOS activity may increase the effectiveness of antimicrobial therapy
PMCID:2929644
PMID: 19745150
ISSN: 1095-9203
CID: 102402

Bacterial NO-synthases operate without a dedicated redox partner

Gusarov, Ivan; Starodubtseva, Marina; Wang, Zhi-Qiang; McQuade, Lindsey; Lippard, Stephen J; Stuehr, Dennis J; Nudler, Evgeny
Bacterial NO-synthases (bNOSs) are smaller than their mammalian counterparts. They lack an essential reductase domain that supplies electrons during NO biosynthesis. This and other structural peculiarities have raised doubts about whether bNOSs were capable of producing NO in vivo. Here we demonstrate that bNOS enzymes from Bacillus subtilis and Bacillus anthracis do indeed produce NO in living cells and accomplish this task by hijacking available cellular redox partners that are not normally committed to NO production. These 'promiscuous' bacterial reductases also support NO synthesis by the oxygenase domain of mammalian NOS expressed in E. coli. Our results suggest that bNOS is an early precursor of eukaryotic NOS and that it acquired its dedicated reductase domain later in evolution. This work also suggests that alternatively spliced forms of mammalian NOSs lacking their reductase domains could still be functional in vivo. On a practical side, bNOS-containing probiotic bacteria offer a unique advantage over conventional chemical NO-donors in generating continuous, readily controllable physiological levels of NO, suggesting a possibility of utilizing such live NO-donors for research and clinical needs
PMCID:2442334
PMID: 18316370
ISSN: 0021-9258
CID: 76130

Bacillus anthracis-derived nitric oxide is essential for pathogen virulence and survival in macrophages

Shatalin, Konstantin; Gusarov, Ivan; Avetissova, Ekaterina; Shatalina, Yelena; McQuade, Lindsey E; Lippard, Stephen J; Nudler, Evgeny
Phagocytes generate nitric oxide (NO) and other reactive oxygen and nitrogen species in large quantities to combat infecting bacteria. Here, we report the surprising observation that in vivo survival of a notorious pathogen-Bacillus anthracis-critically depends on its own NO-synthase (bNOS) activity. Anthrax spores (Sterne strain) deficient in bNOS lose their virulence in an A/J mouse model of systemic infection and exhibit severely compromised survival when germinating within macrophages. The mechanism underlying bNOS-dependent resistance to macrophage killing relies on NO-mediated activation of bacterial catalase and suppression of the damaging Fenton reaction. Our results demonstrate that pathogenic bacteria use their own NO as a key defense against the immune oxidative burst, thereby establishing bNOS as an essential virulence factor. Thus, bNOS represents an attractive antimicrobial target for treatment of anthrax and other infectious diseases
PMCID:2242674
PMID: 18215992
ISSN: 1091-6490
CID: 75858

Instant adaptation to oxidative stress in bacteria is mediated by NO [Meeting Abstract]

Gusarov, I; Nudler, E
ISI:000238400500011
ISSN: 1089-8603
CID: 64819

NO-mediated cytoprotection: instant adaptation to oxidative stress in bacteria

Gusarov, Ivan; Nudler, Evgeny
Numerous sophisticated systems have been described that protect bacteria from increased levels of reactive oxygen species. Although indispensable during prolonged oxidative stress, these response systems depend on newly synthesized proteins, and are hence both time and energy consuming. Here, we describe an 'express' cytoprotective system in Bacillus subtilis which depends on nitric oxide (NO). We show that NO immediately protects bacterial cells from reactive oxygen species by two independent mechanisms. NO transiently suppresses the enzymatic reduction of free cysteine that fuels the damaging Fenton reaction. In addition, NO directly reactivates catalase, a major antioxidant enzyme that has been inhibited in vivo by endogenous cysteine. Our data also reveal a critical role for bacterial NO-synthase in adaptation to oxidative stress associated with fast metabolic changes, and suggest a possible role for NO in defending pathogens against immune oxidative attack
PMCID:1236549
PMID: 16172391
ISSN: 0027-8424
CID: 76138

Novel mechanism of bacterial oxidative stress defense activation by NO [Meeting Abstract]

Gusarov, I; Nudler, E
ISI:000224022300115
ISSN: 1089-8603
CID: 48914

Analysis of the intrinsic transcription termination mechanism and its control

Nudler, Evgeny; Gusarov, Ivan
PMID: 14712715
ISSN: 0076-6879
CID: 46280

Methods of walking with the RNA polymerase

Nudler, Evgeny; Gusarov, Ivan; Bar-Nahum, Gil
PMID: 14712698
ISSN: 0076-6879
CID: 46282

Control of intrinsic transcription termination by N and NusA: the basic mechanisms

Gusarov I; Nudler E
Intrinsic transcription termination plays a crucial role in regulating gene expression in prokaryotes. After a short pause, the termination signal appears in RNA as a hairpin that destabilizes the elongation complex (EC). We demonstrate that negative and positive termination factors control the efficiency of termination primarily through a direct modulation of hairpin folding and, to a much lesser extent, by changing pausing at the point of termination. The mechanism controlling hairpin formation at the termination point relies on weak protein interactions with single-stranded RNA, which corresponds to the upstream portion of the hairpin. Escherichia coli NusA protein destabilizes these interactions and thus promotes hairpin folding and termination. Stabilization of these contacts by phage lambda N protein leads to antitermination
PMID: 11719185
ISSN: 0092-8674
CID: 26542