Innovative Antibiotic Development: New Strategies, Targets and Drugs

The development of antibiotics was one of the most important success stories in human medicine in the 20th century.  Antibiotics have saved millions of lives and eased suffering in countless patients.  Although they have been dubbed “miracle druges,” antibiotics are not always effective.  Over time, bacteria develop resistance to existing drugs, making infections difficut if not impossible to treat.

Antibiotic resistance in pathogenic bacteria has enormous human and economic consequences.  About 2 million people acquire bacterial infections in U.S. hospitals each year, and 90,000 die as a result.  About 70% of those infections are resistant to at least one drug.  The trend towards increasing numbers of infection shows no sign of abating, and the pace at which drug resistance increases is accelerating!  Reistant bacteria lead to higher health care costs because they often require more expensive drugs and extendend hospitatl stays.  The total cost to U.S. society is estimated at $30 billion annually.

Antibiotic drugs have been a big business.  Four individual compounds are billion-dollar drugs, and as a category they account for $23 billion in world-wide sales, making them the second largest therapeutic category in terms of sales.  Until recently, research and development (R&D) efforts have provided new drugs in time to treat bacteria that became resistant to older antibiotics.  That is no longer the case.  Over the past 60 years, a total of ten new classes of antibiotics have been discovered, but only two of these were in the past 40 years.  Since 1998, only 10 new antibiotics were approved by the FDA, two of which were truly novel.  In 2002, among 89 new medicines emerging on the market, none was an antibiotic.  Particularly disturbing is that there is no antibiotic class for which a bacterial resistance mechanism does not already exist.  Unfortunately, most of the large pharmaceutical companies have ended or down-sized their antibiotic R&D efforts and do not have new antibiotic drugs in the pipeline.  A recent study estimates that an aggressive R&D program initiated today would likely require 8 to 10 years and an investment of $800 million to $1.7 billion to bring a new drug to market. In part, the rate at which antibiotic resistance to a drug arises is a major profit-killer for pharmaceutical companies and does not encourage the allocation of substantial resources to the problem.

Because new classes of antibiotics will be slow in coming, perhaps a shift in thinking is necessary.  The focus should not solely be on finding new ways to combat bacteria, but also on finding ways to combat antibiotic resistance directly.  If ways to inhibit the development and spread of resistance could be discovered, the usefulness of currently available effective antibiotics would be extended several years and billions of dollars in additional sales would be realized.  In turn, these benefits would provide time and resources to develop new classes of antibiotics.

Although the mechanisms by which antibiotic resistance evolves and spreads are not fully understood, the rapid rate at which bacteria develop drug resistance is largely due to mutations arising during mutagenic DNA synthesis and gene transfer between organisms.  One protein central to both the development and transmission of antibiotic resistance is RecA, which is found in almost all bacteria likely plays similar roles in all species.  RecA is activated when the bacterium is under stress and cannot divide in the usual way.  RecA acts as the foreman for a crew of repairman.  When activated, the RecA molecules link up, forming a loose chain that wraps around the DNA strands in a right-handed helix like a spring.  Adenosine triphosphate (ATP) gives the spring the energy to extend and stretch the DNA molecule, allowing the relatively rigid double-helix structure the flexibility it needs to repair itself by shuffling base pairs around.  In addition, the extended chain initates the actions of other enzymes that act to copy the DNA in a sloppy fashion.  This is known as the “SOS response.”  Thus, RecA’s actions can shuffle genes between bacteria or cause new genes to be developed from old ones.

Our work focuses on ways to suppress RecA’s actions.  We hope to create a drug that would cause bacteria to become RecA deficient, opening up a number of therapeutic possibilities. Our research could create a new class of antibiotics or make bacteria more susceptible to existing antibiotics, allowing patients to take much lower doses of powerful drugs such as mytomycin, a genotoxin that damages human as well as bacterial DNA. Drugs of this type are currently treatments of last resort because they can be as dangerous to the patient as they are to the bacteria.  The “synergism” between drugs targeting RecA and current antibiotics would render the antibiotic more effective at the outset, which is of paramount importance when dealing with bacterial bioterrorism agents where pluripotent action is essential.  Using a RecA inhibitor in combination with mitomycin C, ciprofloxacin, or another DNA damaging antibiotic could provide a therapeutic strategy for treating NIAID class A and B pathogens.

Most exciting to us is the potential to suppress a bacterial population’s ability to develop drug resistance.  When under attack by medicines and on the brink of destruction,  bacteria initiate what is know as the “SOS response,” pulling out all the stops by mutating themselves in a desperate gambit to survive.  RecA initiates and controls the SOS response. Without RecA, the bacteria would be unable to develop antibiotic resistance.

We are currently working on (or have plans for) developing inhibitors of RecA for use in a number of pathognic bacteria, including Escherichia coli, Neisseria gonorrhoeae, Pseudomonas aeruginosa, Vibrio cholerae, Bacillus anthracis, Salmonella enterica, and Acinetobacter baumannii.

Our efforts encompass several classes of synthetic inhibitors, including ATP-comptetitve small molecules, designed peptides, and select organometallic complexes.  In addition, we have initated programs in anti-gene approaches, including the use of peptide-nucleic acids (PNAs) to inhibit gene transcription and a novel approach for inhibiting protein translation by messenger RNA destruction.