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Turning down tolerance Persister cells, which are found in abundance in biofilms, adopt a quiescent state and survive antimicrobial treatments, seeding disease recurrence and incubating new resistance mutations. Building on work implicating the reactive small-molecule hydrogen sulfide in bacterial defense against antibiotics, Shatalin et al. conducted a structure-based screen for inhibitors of a bacterial hydrogen sulfide–producing enzyme and found a group of inhibitors that act through an allosteric mechanism (see the Perspective by Mah). These inhibitors potentiated bactericidal antibiotics in vitro and in mouse infection models. They also suppressed persister bacteria and disrupted biofilm formation. This strategy of taking out persister cells may be promising for treating recalcitrant infections and holding the line against drug-resistant bacteria. Science , abd8377, this issue p. 1169 ; see also abj3062, p. 1153

Many prokaryotic species generate hydrogen sulfide (H(2)S) in their natural environments. However, the biochemistry and physiological role of this gas in nonsulfur bacteria remain largely unknown. Here we demonstrate that inactivation of putative cystathionine β-synthase, cystathionine γ-lyase, or 3-mercaptopyruvate sulfurtransferase in Bacillus anthracis, Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli suppresses H(2)S production, rendering these pathogens highly sensitive to a multitude of antibiotics. Exogenous H(2)S suppresses this effect. Moreover, in bacteria that normally produce H(2)S and nitric oxide, these two gases act synergistically to sustain growth. The mechanism of gas-mediated antibiotic resistance relies on mitigation of oxidative stress imposed by antibiotics.

It's a Gas Many antibiotics, including beta-lactams, aminoglycosides, and quinolones, kill bacteria (at least in part) by oxidative stress. Gusarov et al. (p. 1380 ) show that nitric oxide (NO) produced by bacterial NO synthases (bNOS) protects bacteria, including Staphylococcus aureus and Bacillus anthracis , against toxic agents they may encounter in the soil or in host organisms. Thus, bNOS activity is specifically induced in response to antibiotics and, in turn, activates the expression of another key antioxidant enzyme: superoxide dismutase. Hence, NO-mediated antibiotic resistance not only operates by direct chemical modification of toxic molecules, but also alleviates oxidative stress caused by naturally occurring antibiotics.