Mechanisms of Antibiotic Resistance and the Impact of Drug Resistance on the Development and Use of Antibiotics

Antibiotics have represented the primary line of defense for treating bacterial infections since 1935 when the first sulfur-containing compounds were introduced. Many antibiotic compounds are produced naturally by microorganisms while some more recently developed antibiotics are chemically designed based on a knowledge of susceptible biochemical pathways or physiological processes in pathogenic bacteria. Ciprofloxacin (“cipro”), a synthetic broad-spectrum antibiotic, functions by interfering with DNA replication.

Increased use and mis-use of antibiotics has led to increased numbers of pathogenic bacteria that are resistant to one or more antibiotics. Some resistant microbes possess mechanisms that allow continued growth in the presence of multiple antibiotics. These multiply drug-resistant pathogenic bacteria may also possess pathogenic properties that result in significantly more severe disease than their drug-sensitive cousins. Medical misuse of antibiotics – prescribing antibiotics for viral infections, failure of patients to complete treatment with the full regiment of antibiotics, or application of antibiotics based on inaccurate or incomplete tests can lead to selection of antibiotic resistant bacteria that can then cause infections that cannot be treated with the antibiotic(s) to which they are resistant. Multiple drug resistance can quickly reduce or eliminate all antibiotic-based treatment options. Infections caused by antibiotic resistant bacteria are very difficult to treat and can sometimes lead to death of the patient.

Antibiotic resistance can also result from selection based on exposure to antibiotics present in the environment. More than 70% of the antibiotics sold in the U.S. are used as supplements to animal feed. The intestinal bacteria in the animals provided with such feed often show resistance to the antibiotics in the feed and, in some documented cases, have transferred this resistance to pathogenic microbes with which they share the environment.

A brief of history of antibiotic use and the medical and public policy factors that are, in part, responsible for increased antibiotic resistance in pathogenic microbes and for a decrease in the development of new antibiotics will be presented. An introduction to new directions that are being taken to develop a next generation of antibiotic compounds will also be provided.

Speaker Biography:

Paul Jackson received his Bachelor's of Science degree from the University of Washington in Cellular Biology and his Ph.D. from the University of Utah in Molecular Biology. He became a CISAC Visiting Scholar in September 2011. He was previously a CISAC affiliate.

For the past 18 years he has been studying bacterial pathogens, first working to develop DNA-based methods of detecting these microbes and their remnants in environmental and laboratory samples, then developing methods to differentiate among different strains of the same pathogenic species. Research interests include the study of different methods of interrogating biological samples for detection and characterization of content, and development of bioforensic tools that provide detailed information about biothreat isolates including full interrogation of samples for strain content and other genetic traits.

Methods he developed have been applied to forensic analysis of samples and aid in identifying the source of disease outbreaks. He contributed to analysis of the Bacillus anthracis present in the 2001 Amerithrax letters and conducted detailed analyses of human tissue samples preserved from the 1979 Sverdlovsk anthrax outbreak, providing evidence that was inconsistent with Soviet government claims of a natural anthrax outbreak.

His current work continues to focus on development of assays that rapidly detect specific signatures including antibiotic resistance in threat agents and other pathogens. More recent activities include identification and characterization of new antimicrobial compounds that are based on the pathogens' own genes and the products they encode. These include development of such materials as therapeutic antimicrobials, their application to remediate high value contaminated sites and materials, and their use to destroy large cultures and preparations of different bacterial threat agents. Efforts to address issues of antibiotic resistance and treatment of resistant organisms have recently been expanded to look at non-threat agent pathogens that cause problematic nosocomial or community-acquired infections of particular interest to the military.

Paul spent 24 years as a Technical Staff Member at Los Alamos National Laboratory where he was heavily involved in development of the biological threat reduction efforts there. He was appointed a Laboratory Fellow at Los Alamos in recognition of his efforts. He moved to Lawrence Livermore National Laboratory in 2005 where he is presently Senior Scientist in the Global Security and Physical and Life Sciences Directorates. In addition to his work at the National Laboratories, he has served on the FBI's Scientific Working Group for Microbial Forensics, on NIH study sections and review panels, and continues to serve on steering and oversight committees for other federal agencies.