Renewing the Fight Against Bacteria

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http://www.the-scientist.com/yr2002/mar/wilson_p22_020304.html

The Scientist 16[5]:22, Mar. 4, 2002

NEWS

Renewing the Fight Against Bacteria

Scientists are trying to re-harness the power of antibiotics

By Fisher

Courtesy of Aventis Pharmaceuticals

Fighting Resistance: Bacteria culture used in the lab for developing new

antibiotics

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In the 1940s, the mass production of penicillin led to a sensational

reduction in illness and death from bacterial disease. A resulting golden

era of bacterial research emerged with new classes of antibiotics, and by

1969, US Surgeon General H. told Congress: " The time has

come to close the book on infectious disease. "

As a result, fewer new students specialized in bacterial physiology, and

federal funders shifted their focus to more immediately pressing diseases,

as did many pharmaceutical companies. But while everyone forgot about the

bacteria, the bacteria didn't completely abandon their unwilling hosts.

Today, nearly all strains of Staphylococcus aureus, an organism that causes

skin, bone, lung, and bloodstream infections, now resist penicillin. Many do

the same to methicillin, and some even resist vancomycin, long considered

the only uniformly effective drug for methicillin-resistant S. aureus,

according to the Centers for Diseases Control and Prevention (CDC). The

agency also estimates that 30% of Streptococcus pneumoniae-caused pneumonia,

meningitis, and ear infections no longer respond to penicillin. In fact,

about 70% of bacteria found in hospitals resist at least one of the drugs

most commonly used to treat infection, according to CDC estimates.

Antibiotics resistance continues to increase; much of it occurs from misuse.

Physicians in the United States write about 50 million pointless antibiotic

prescriptions each year for colds and other viral infections, the CDC

estimates.

While signs of resistance first appeared decades ago, it wasn't until the

mid-1990s that medical organizations such as the American Medical

Association and the American College of Physicians-American Society for

Internal Medicine, provided doctors with antibiotic resistance education and

guidelines to properly prescribe. Even today, " I don't think many physicians

and other people are convinced that this is a problem, because they still

can cure most bacterial infections, even if it takes a few tries to find the

right antibiotic, " says Abigail Salyers, bacterial physiologist at the

University of Illinois and president of the American Society of

Microbiology.

Many factors increase the risk of bacterial infection and subsequent

resistance, says Steve Projan, director of antibacterial research at

Wyeth-Ayerst in Pearl River, NY. These factors include growing population

densities and an increasingly immunosuppressed population. " People have

forgotten what it was like before antibiotics: If you had Staph in your

bloodstream, the infection was fatal at least 90% of the time, " Projan says.

Thanks to bacterial pathogen genomes, however, some pharmaceutical companies

are using a target-based approach to come up with some new

infection-fighting answers.

Role of Basic Research

Courtesy of Aventis Pharmaceuticals

Alive and Well: Not all drug companies have abandoned antibiotic research as

shown here in the lab at Aventis Pharmaceuticals.

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Scientists have left the bacterial research field in droves for newer

fields including genomics and molecular biology. Meanwhile, universities

have widely phased out microbiology, or merged it into other departments,

leaving few faculty members to encourage young scientists into the field,

Salyers says. In recent decades, the National Institutes of Health's shift

to newer priorities such as viral infections and AIDS hasn't helped either.

" After bacteriologists produced the molecular revolution, it was easy to

think, 'well, we've done that and now we can move on.' It became

unfashionable to pursue bacteria, " she adds.

Very little is known about the diverse genetic structure of bacteria,

according to Salyers. As yet, scientists can't recognize the function of

one-third of the open reading frames-the DNA region that encodes for

specific proteins and bases of the coding sequence-in model bacterium

Escherichia coli. Any realistic analysis of the bacterium's genome sequence

is impossible, she says.

Moreover, little is known about the complex mechanisms by which bacteria

change and become drug resistant. Salyers' own work has uncovered how an

intestinal bacterium, Bacteroides, typically becomes resistant to

antibiotics through DNA transfer, not by the more widely understood

mechanism of gene mutation.1 " We still have a lot to learn in the area of

bacterial metabolism and physiology, " confirms Rita Colwell, microbiologist

and director of the National Science Foundation.

It's time for an attitudinal change in the wider scientific community to

recognize the importance of bacterial research, both women say. Salyers and

others note that increased funding would show researchers just how important

this field is. " Many scientists think that we know as much as we need to

know about bacteria and that chemists and biochemists should take the lead

in development of antibiotics, but there's no substitute for understanding

bacterial physiology better, " Salyers says.

Role of Pharmaceutical Industry

After decades of success in discovering antibiotics, pharmaceutical

companies have struggled in recent years to find new, broad-spectrum

compounds. Cost concerns and a failure to find new prospects have led

Novartis, GlaxoKline, Bristol-Myers Squibb Co., Eli Lilly and Co., and

other major drug companies to downsize or exit the antibiotics market. Focus

has shifted to developing drugs with greater potential long-term profits,

particularly for treating chronic conditions such as high blood pressure.

" You don't want to spend a lot of time and money developing an antibiotic

and then discover after a few years that you can't use it for what it was

designed to treat because of resistance, " says Alan Goldhammer, associate

vice president, regulatory affairs for PhRMA, the Washington, DC,

representative group for the pharmaceutical industry.

Not all drug companies have abandoned antibiotics, however. Antibiotics are

still the second-largest drug market after cardiovascular therapeutics, and

at least five such drugs earn more than $1 billion for their companies,

including Cipro (ciprofloxacin hydrochloride, Bayer), Zithromax

(azithromycin, Pfizer), and Augmentin (amoxicillin/clavulanate potassium,

GlaxoKline), Projan notes. A November 2000 PhRMA report surveyed US

pharmaceutical and biotechnology industries and found 19 antibiotics

currently in development. Two new ones hit the market in 2001, Invanz

(ertapenem sodium) from Merck & Co. and Ketek (telithromycin) from Aventis

Pharmaceuticals.

The opportunity to identify novel antibacterials using a new target-based

approach, founded on the sequencing of bacterial pathogen genomes, has

sparked a resurgence in antibiotic research, says Hodgson, head of

infectious diseases for Aventis. " Many saw this as an opportunity to make

some quick progress in developing new antibacterials, but, while genomics

has provided a plethora of new antibacterial targets, it takes a long time

to develop a new drug, " he says.

One of the first compounds to emerge from this target-based approach is a

peptide deformylase inhibitor from British Biotech, which could enter

clinical trials this year. Additionally, companies are seeking to develop

new agents from new knowledge regarding the host response to bacterial

infection, particularly those effective against sepsis, a highly fatal,

hospital-acquired bacterial disease, Hodgson says. The first marketed new

drug against sepsis based on this approach, Xigris (drotrecogin alfa

[activated], Lilly) received Food and Drug Administration approval late last

year.

Government Addresses Antibiotic Resistance

Courtesy of Bristol-Myers Squibb

The Enemy: Penicillin-resistant Streptococcus pneumoniae

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Government sources emphasize that adequate research funding is available,

but only to those conducting high-quality bacterial research. The problem is

that US investigation into this area just isn't robust, says Marissa ,

antimicrobial resistance program officer with the Division of Microbiology

and Infectious Diseases (DMID), National Institutes of Allergy and

Infectious Diseases. " We can't just throw money at this. Then you get a lot

of ... low-quality grants. You have to start small and build over time, " she

says. Senior level researchers, not the NIH, are responsible for

jump-starting the field, she notes. They should sponsor and mentor more

students while the American Society of Microbiology, NIH and NSF increase

educational opportunities and grants for young investigators.

Recently, the DMID announced new grants related to reducing the threat of

bioterrorism. In 2000, they posted a challenge grant that partnered industry

and academic scientists to study resistant infections. A 2002 partnership

grant is modeled on the challenge grant, but doesn't require mandatory

matching of dollars by industry. Investigator-initiated grants are always

another option scientists can pursue, says. Additionally, resources

exist for clinical trials, animal and in vitro testing, she says. Interest

is particularly high in novel approaches to bacterial therapeutics, such as

phage therapy and vaccines.

Moving Forward

An interagency approach would help to focus funds on advancing antibacterial

research, notes . " If we had a Manhattan Project-type of approach, we

could produce some very powerful and highly effective vaccines [and other

antibacterial drugs] against a variety of infectious diseases. "

A 1999 Kennedy-Frist bill that identified antibiotic resistance as a looming

public health problem created an interagency task force, but allocated very

little new funding. Headed by the CDC, the Food and Drug Administration and

the NIH, the task force issued a plan in 2000 to deal with antimicrobial

resistance that includes surveillance of resistance and monitoring of drug

use; prevention and control to develop better diagnostic testing and

infection control and ensure appropriate use of antibiotics; research to

increase understanding of microbial physiology, ecology, genetics and

mechanisms of resistance; and product development to translate research into

clinically useful products and stimulate development of antimicrobial

products. According to , not enough funds are available to fully

implement the plan.

Fisher (jfwilson@...) is a contributing editor.

1. N.B. Shoemaker et al., " Evidence for extensive resistance gene transfer

among Bacteroides spp. and among Bacteroides and other genera in the human

colon, " Applied and Environmental Microbiology, 67:561-8, 2001.