A team of scientists in the US reports they may have a found a new way to make bacteria like MRSA and anthrax more vulnerable to existing antibiotics by interfering with a defence mechanism that the microbes use to resist the oxidative stress imposed on them by antibiotics.

The discovery was led by Dr Evgeny A. Nudler, who is the Julie Wilson Anderson Professor of Biochemistry at New York University (NYU) Langone Medical Center, and is reported in the 11 September issue of Science.

Nudler and colleagues found evidence that nitric oxide (NO), alleviates oxidative stress imposed on bacteria by many types of antibiotic, and it also helps to neutralize many anti-bacterial compounds.

Removing this NO-based defence mechanism makes existing antibiotics more able to fight bacteria at lower and less toxic doses, and opens the door to new ways of fighting bacterial diseases that have become resistant to antibiotics, they told the media.

NO is a tiny and very simple molecule with just one nitrogen and one oxygen atom. It wasn't until the late 1980s that we realized that NO was more than just a toxic gas and air pollutant and also played an important part in regulating the biology of mammals. Since then studies have shows that NO is important in learning and memory, control of blood pressure, penile erection, digestion, fighting infection, and even cancer.

To kill bacteria you can either get them to kill themselves by putting them under prolonged oxidative stress, or you can poison them directly with toxins. Antibiotics use both these mechanisms but unfortunately the more you use them, the higher the chance that bacteria mutate and develop ways to resist oxidative stress and neutralize toxins.

Certain types of bacteria called "gram-positive" bacteria (these types include species such as MRSA and anthrax, and other potentially fatal organisms) make NO by releasing it from NOS (NO-synthase), an enzyme that they make themselves from the common amino acid arginine.

A few years ago, Nudler and his team found that these bacteria use NO to defend against oxidative stress.

With this study they showed that the NO that the bacteria release from their NOS increases their resistance to "a broad spectrum of antibiotics, enabling the bacteria to survive and share habitats with antibiotic-producing microorganisms".

They found that resistance came from two effects: (1) NO helped to modify compounds that were toxic to the bacteria, and (2) it alleviated oxidative stress.

Inhibiting NOS should therefore boost the effectiveness of existing antibiotics that rely on these two mechanisms to kill bacteria, as the researchers concluded:

"Our results suggest that the inhibition of NOS activity may increase the effectiveness of antimicrobial therapy."

Nudler and colleagues suggested that scientists could use commercially available inhibitors to stop the bacteria from releasing the NO.

Nudler told the media that:

"Developing new medications to fight antibiotic resistant bacteria like MRSA is a huge hurdle, associated with great cost and countless safety issues."

"Here, we have a short cut, where we don't have to invent new antibiotics. Instead, we can enhance the activity of well established ones, making them more effective at lower doses," he explained.

"Endogenous Nitric Oxide Protects Bacteria Against a Wide Spectrum of Antibiotics."
Ivan Gusarov, Konstantin Shatalin, Marina Starodubtseva, and Evgeny Nudler.
Science, 11 September 2009: Vol. 325. no. 5946, pp. 1380 - 1384
DOI: 10.1126/science.1175439

Source: NYU.

Written by: Catharine Paddock, PhD