Nitric Oxide Holds Promise for Better Antibiotics

Tough pathogens, such as anthrax and MRSA, depend on nitric oxide to defend themselves against antibiotic drugs, according to recent research. Targeting this line of defense may lead to new tactics for fighting even the nastiest bacterial infections.

Although doctors have prescribed antibiotics to treat infections for well over 50 years, many bacteria have developed resistance to these treatments, prompting drug companies to spend millions of dollars developing alternative forms of the drugs. Even more troublesome have been specific bacteria, including strains of Staphylococcus, which defy most known antibiotics. Yet, with the new discovery of how bacteria defend themselves with nitric oxide, scientists now hope that by merely blocking the site of nitric oxide production in bacteria they can make traditional antibiotics much more potent against even incredibly virulent infections.

“If you make bacterial cells more vulnerable to the old and well-established antibiotics, that is better than having to design new antibiotics,” explains New York University biochemist Evgeny Nudler, who led a research team that recently showed bacteria are virtually defenseless when they are unable to produce nitric oxide. Nudler, along with group members Ivan Gusarov and Konstantin Shatalin, published their findings in a September issue of the journal Science.

Although the nitric oxide molecule is the true culprit — it interrupts the destructive chemical pathway launched by an antibiotic — Nudler believes the best offense against bacteria will be attacking the compound’s production site, known as nitric oxide synthase, or NOS. Drug developers have already identified and tested molecules that block similar NOS enzymes in humans. Although these particular drugs were designed to target the human nitric oxide pathways that are involved in blood pressure disorders, the same technology may be tuned to specifically target bacteria.

Treating bacterial infections with cocktails of traditional antibiotics and NOS inhibitors to prevent nitric oxide formation will be more efficient than designing entirely new drugs, suggests Nudler. An important advantage of this approach is that each of the individual drugs that make up the new therapy have already undergone independent tests for human safety; a combined therapy should therefore not require the arduous drug screening that entirely new antibiotics have to endure.

To test this proposed therapy, Nudler’s team has already moved on to testing drug combinations in mice, with the help of collaborators from the University of California, San Diego.

The recent studies, which both demonstrated nitric oxide’s role in helping bacteria stave off the effects of antibiotics and paved the way for its potential therapeutic applications, have excited Nudler’s colleagues.

“This work very nicely demonstrates that bacteria that produce nitric oxide use it to protect themselves against the lethal effects of antibiotics, and that this is a broad effect,” says Jim Collins, a biomedical engineer at Boston University. Collins studies how antibiotics act to promote bacteria death.

While antibiotics have long been used to fight bacteria, exactly how the drugs caused cell death remained a mystery until 2007, when Collins’ group demonstrated that many antibiotics rely on destructive oxidizing agents in order to ravage the bacteria from the inside out.

But if this was the poison, the question remained: what did the bacteria use as an antidote to help themselves stay alive? The identification of nitric oxide’s role in bacterial defense has provided a valuable answer, one that might make researchers reevaluate antibiotic design.

With his studies of a dual-drug system already underway in mice, Nudler believes they can quickly evaluate this new strategy. “The endpoint is very clear,” he says. “You clean out an infection or not. If it works, you can easily see it.”