The Fight Against Antibiotic-Resistant Pathogenic Bacteria: A New Era

Abstracts

The Confounding Issues Regarding Antibiotic Resistance — A No-Win Battle!
Barry Kreiswirth, PhD, UMDNJ

In 1969, Surgeon General William H. Stewart declared an end to the era of infectious diseases, as antibiotic pipelines were overflowing and the threat of drug resistant strains limited. What Stewart could not predict was the large increase in immunosuppressed patients, both the result of HIV disease and active suppression for transplantation surgery and other heroic medical efforts. As such, advancements in medicine enabled patients with otherwise life threatening diseases to live longer, commonly with the aid of anti-infectives. After 70 years of unabated use, the effectiveness of our most potent antimicrobials are being compromised evidenced in the remarkable and rapid evolution of drug resistance mechanisms, many on mobile genetic elements that are able to spread within and between species. The recent emergence of community acquired methicillin resistant S. aureus (MRSA), extensively drug resistant (XDR) M. tuberculosis and carbapenem resistant Enterobacteriaceae are highly drug resistant strains that have limited treatment options. Compounding this problem is the hollow antibiotic pipeline, the absence of antibiotic discovery programs in most pharmaceutical companies, and the limited success in developing novel compounds. Advancements in diagnostics, including real-time nucleic amplification platforms at the bedside, can enhance prudent use of antibiotics however has yet to be integrated in our healthcare setting. The gravity of antibiotic resistance has consequently led to alternative strategies, including phage therapy, antibody treatment, inhibitory peptides, and immunomodulators; but similar to our dependence on oil, we remain hooked on antibiotics, even though they too may go the route of the dinosaur.
 

Using What Bacteriophage Have Learned to Develop Novel Tools for Treating Gram-positive Infections
Vincent A. Fischetti, PhD, The Rockefeller University

With mounting antibiotic resistance, new anti-infectives must be developed to remain one step ahead of pathogenic bacteria. Bacteriophages have evolved with bacteria for about a billion years. During this time phage have evolved systems that may be exploited to kill bacteria. The lytic system consists of a holin and at least one lysin capable of degrading the bacterial cell wall. Lysins act on bonds in the peptidoglycan resulting in cell lysis and release of progeny phage. While lysins have been known for decades, they have been recently used in their purified form to kill pathogenic bacteria on mucous membrane surfaces, infected tissues and in blood. Nanogram to sub-microgram quantities of purified lysin per milliliter is sufficient to sterilize a 107 bacterial suspension in seconds to minutes. To date, other than chemical agents, there is no biological compound known that can kill bacteria this quickly. Since nearly all bacteria are or can be infected by bacteriophage, such enzymes may be developed for nearly all disease-causing gram-positive bacteria. The Fischetti lab has recombinantly produced phage lysins that kill the major gram-positive pathogens—Streptococcus pyogenes, Streptococcus pneumoniae, Staphylococcus aureus, Enterococcus faecalis, group B streptococci and Bacillus anthracis—and has used these enzymes to destroy their respective bacteria in animal models of disease. A more detailed understanding of phage lysins has revealed that the binding domain of these enzymes have evolved to target essential structures in the gram-positive cell wall. Using this information, strategies have been developed to identify novel pathways in the gram-positive organism that are targets for antibiotics with reduced potential for resistance.