Blocking Nitric Oxide Formation May Increase Effectiveness of Antibiotics

Nitric oxide (NO) generated by nitric oxide synthases (NOS) in some Gram-positive bacteria increases the resistance of the bacteria to a broad spectrum of antibiotics, so drugs that inhibit NOS activity may increase the effectiveness of antimicrobial therapy.

Nitric oxide is a crucial physiologic messenger molecule that is thought to play a role in blood pressure regulation, control of blood clotting, immune defense, digestion, the senses of sight and smell, and possibly learning and memory. Nitric oxide may also participate in disease processes such as diabetes, stroke, hypertension, impotence, septic shock, and long-term depression. Nitric oxide can freely diffuse through aqueous solutions or membranes, reacting rapidly with metal centers in cellular proteins and with reactive groups in other cellular molecules.

Investigators from the New York University School of Medicine (New York, USA) earlier had shown that bacteria mobilize NO to defend against oxidative stress. In the current study, which was published in September 11, 2009, issue of the journal Science, the authors demonstrated that many antibiotics cause oxidative stress in bacteria, often resulting in their death, and that NO opposes this effect.

In addition to alleviating oxidative stress NO provided further protection to the bacteria by chemically modifying toxic compounds. The authors therefore suggested that commercially available inhibitors of NOS could render antibiotic resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and anthrax more sensitive to available drugs.

"Developing new medications to fight antibiotic resistant bacteria like MRSA is a huge hurdle, associated with great cost and countless safety issues," said senior author Dr. Evgeny A. Nudler, a professor of biochemistry at the New York University School of Medicine. "Here, we have a short cut, where we do not have to invent new antibiotics. Instead, we can enhance the activity of well established ones, making them more effective at lower doses."

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New York University School of Medicine