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Drugs unable to keep up with resistant bacteria

By Richard Brill

LAST UPDATED: 8:52 p.m. HST, Aug 5, 2011

The Oct. 26, 2007, edition of the New York Post carried the headline "Superbug Strikes in City." It was not a horror movie.

Certain bacteria become resistant to even the most potent antibiotics. Natural selection is the culprit.

Methicillin-resistant Staphylococcus aureus, or MRSA, causes 19,000 deaths annually in the United States, more than HIV/AIDS. Treating MRSA in U.S. hospitals costs upward of $3 billion annually, and it is only one pathogen that is becoming drug resistant.

Some resistance develops through random mutations, and nearby bacteria can transfer some, even to different species.

Cells can transfer pieces of DNA called plasmids that the new host recognizes as a native piece of DNA and then passes on during replication. A plasmid isolated from a sewage treatment plant encoded nine different genes for antibiotic resistance.

A particularly challenging group of bacteria is Gram-negative.

The Danish scientist Hans Christian Gram (1853-1938) developed Gram-staining in 1884 to discriminate between Klebsiella pneumoniae and Streptococcus pneumoniae. Gram-negative Klebsiella pneumoniae cause pneumonia but also infect surgical wounds and urinary tracts. Gram-negative bacteria easily exchange plasmids so that a resistant gene that arises in Klebsiella quickly migrates to E. coli and other Gram-negative species.

The plasmid transfer to E. coli raises the probability that the resistant gene will not stay confined to hospitals, but will move into the everyday world carried in human gut bacteria, advancing undetected via handshakes, kisses and doorknobs.

Two important resistant genes make Klebsiella resistant to many antibiotics including the carbapenems, a group of so-called last-resort antibiotics.

Carbapenem resistance in Gram-negative bacteria is alarming because they share genes easily, they are ubiquitous and pharmaceutical companies are not making many new antibiotics. Against the stubborn Gram-negatives, they have no new compounds in the pipeline at all.

Over the decades, the seesaw battle between bacteria and antibiotics has gradually tilted in favor of the organisms. Even responsible use of antibiotics drives the emergence of resistance by exerting selective pressure on the cells to adapt. It takes bacteria only 20 minutes to produce a new generation, but it takes a decade or more to research and develop a new antibiotic.

One reason for a 40-year innovation gap in antibiotic classes is a lack of economic incentive. There is little motivation to invest in antibiotic research with small profit margins compared with lifestyle drugs such as those for high blood pressure, cholesterol or diabetes.

Another reason is that current antibiotics were discovered by techniques that are now dated, and finding new ones requires novel discovery strategies.

Antibiotics made from organisms in exotic settings are desirable as they are more likely to make new antibiotics to which both Gram-negative and Gram-positive bacteria have yet to develop resistance.

A sediment sample from a depth of 950 feet in the Sea of Japan produced a new antibiotic, while the genomes of two formerly unknown marine strains revealed a diverse array of genes for antibiotics and related molecules. These and other marine bacteria show great potential to yield new classes of antibiotics.

Hopefully these will come soon enough to tip the balance away from bacteria.

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