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首页> 外文期刊>PLOS Neglected Tropical Diseases >Nitric Oxide from IFNγ-Primed Macrophages Modulates the Antimicrobial Activity of β-Lactams against the Intracellular Pathogens Burkholderia pseudomallei and Nontyphoidal Salmonella
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Nitric Oxide from IFNγ-Primed Macrophages Modulates the Antimicrobial Activity of β-Lactams against the Intracellular Pathogens Burkholderia pseudomallei and Nontyphoidal Salmonella

机译：干扰素γ巨噬细胞中的一氧化氮调节β-内酰胺对细胞内病原菌假单胞菌和非伤寒沙门氏菌的抗菌活性

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Our investigations show that nonlethal concentrations of nitric oxide (NO) abrogate the antibiotic activity of β-lactam antibiotics against Burkholderia pseudomallei, Escherichia coli and nontyphoidal Salmonella enterica serovar Typhimurium. NO protects B. pseudomallei already exposed to β-lactams, suggesting that this diatomic radical tolerizes bacteria against the antimicrobial activity of this important class of antibiotics. The concentrations of NO that elicit antibiotic tolerance repress consumption of oxygen (O2), while stimulating hydrogen peroxide (H2O2) synthesis. Transposon insertions in genes encoding cytochrome c oxidase-related functions and molybdenum assimilation confer B. pseudomallei a selective advantage against the antimicrobial activity of the β-lactam antibiotic imipenem. Cumulatively, these data support a model by which NO induces antibiotic tolerance through the inhibition of the electron transport chain, rather than by potentiating antioxidant defenses as previously proposed. Accordingly, pharmacological inhibition of terminal oxidases and nitrate reductases tolerizes aerobic and anaerobic bacteria to β-lactams. The degree of NO-induced β-lactam antibiotic tolerance seems to be inversely proportional to the proton motive force (PMF), and thus the dissipation of ΔH+ and ΔΨ electrochemical gradients of the PMF prevents β-lactam-mediated killing. According to this model, NO generated by IFNγ-primed macrophages protects intracellular Salmonella against imipenem. On the other hand, sublethal concentrations of imipenem potentiate the killing of B. pseudomallei by NO generated enzymatically from IFNγ-primed macrophages. Our investigations indicate that NO modulates the antimicrobial activity of β-lactam antibiotics.
机译：我们的研究表明，非致死浓度的一氧化氮（NO）消除了β-内酰胺类抗生素对假伯克霍尔德氏菌，大肠杆菌和非伤寒性肠炎沙门氏菌鼠伤寒的抗菌活性。 NO保护已经暴露于β-内酰胺类的假芽孢杆菌，表明该双原子基团可耐受细菌抵抗这一重要类抗生素的抗菌活性。引起抗生素耐受性的NO浓度会抑制氧气（O2）的消耗，同时刺激过氧化氢（H2O2）的合成。转座子在编码细胞色素C氧化酶相关功能和钼同化的基因中的插入赋予假芽孢杆菌对抗β-内酰胺类抗生素亚胺培南的抗菌活性的选择性优势。累积地，这些数据支持一个模型，通过该模型，NO可以通过抑制电子传输链来诱导抗生素耐受性，而不是通过增强先前提出的抗氧化剂防御能力来实现。因此，末端氧化酶和硝酸盐还原酶的药理学抑制作用使需氧和厌氧细菌耐受β-内酰胺。 NO诱导的β-内酰胺类抗生素耐受性的程度似乎与质子动力（PMF）成反比，因此，PMF的ΔH+和ΔΨ电化学梯度的耗散阻止了β-内酰胺介导的杀伤。根据该模型，由IFNγ引发的巨噬细胞产生的NO保护细胞内沙门氏菌免受亚胺培南的侵害。另一方面，亚致死浓度的亚胺培南可增强由IFNγ引发的巨噬细胞酶促产生的NO杀死假苹果芽孢杆菌。我们的研究表明，NO调节β-内酰胺类抗生素的抗菌活性。

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