Drug Resistant Bacteria — A Research Challenge
There has been much ado about drug resistant bacteria in the news. As a researcher in the field, I thought it would be valuable to outline some of the biochemical background that explains some of the challenges in this field.
Most bacteria require a cell wall to live. Enzymes named D-alanyl-D-alanine carboxypeptidases (peptidases) are responsible for forming the bacterial cell wall. Beta-lactam antibiotics (i.e. penicllins, cephalosporins, carbapenams, and monobactams) are useful because they inhibit the mechanism peptidases use for bacterial cell wall formation.
However, in response to environmental factors, bacteria have been evolving for millions of years to circumvent these problems. One resistance mechanism is the development of a competing enzyme known as a beta-lactamase. They have a similar binding site therefore compete with peptidases to bind beta-lactam antibiotics. When a beta-lactamase binds a beta-lactam antibiotic it is rendered useless against their intended target, peptidases.
One of the main problems surrounding research today is that beta-lactamases have become better at binding most antibiotics than peptidases. However, this is not the only method of drug resistance, similarly, beta-lactams are not the only class of antibiotics encountering resistance. For example, bacterial mutations can occur making drug resistance a multifaceted problem. This has resulted in a world wide health crisis. Researchers are scrambling to design new antibiotics to overcome the propagating issue.
The term ‘superbug’ is being used to denote multi-drug resistant (MDR) bacteria. MRSA (methicillin-resistant Staphylococcus aureus), a well known super bug, is common in densely populated areas particularly hospitals, prisons, and athletic locker rooms. A great deal of research is underway to develop effective antibiotics for MRSA, a gram-positive bacteria. In the last two decades, only two new classes of antibiotics (daptomycin and linezolid) have been introduced and are gram-positive specific. Despite this development, MRSA is still a prevalent problem.
This leads to another issue, not all bacteria are gram-positive, additionally, some are gram-negative. In general, there has been less research focused on gram-negative bacterial infections. In 2008, a new beta-lactamase was identified in Klebsiella pneumoniae in India now named the New Delhi metallo-beta-lactamase (NDM-1). This enzyme is able to inhibit all beta-lactams except aztreonam, however its mechanisms make it resistant to nearly all antibiotics. NDM-1 is becoming prevalent in a variety of bacterial strains creating significant complications and a new target for researchers.
We are basically in a ‘keeping up with the Joneses’ relationship with bacteria. We develop new drugs and they evolve.
Research is consistently being done to help solve these problems. A common strategy is to combine a beta-lactamase inhibitor with a beta-lactam antibiotic. Therefore the inhibitor prevents the beta-lactamase from interfering with the antibiotic activity of the beta-lactam in peptidases.
Just this week, I have read a couple promising papers about beta-lactamase inhibitors. The group of Christian Melander at NC State University published a study in Medicinal Chemistry Letters that resulted in a promising drug that acts as a partner to an antibiotic. Their drug binds to NDM-1 and allows the antibiotic to inhibit K. pneumoniae growth. At University of South Florida, Yu Chen’s group published in the Journal of Medicinal Chemistry another beta-lactamase inhibitor for the CTX-M class.
Multi-drug resistant bacteria is a world wide problem and nothing short of consistent, collaborative research will allow us to ‘keep up’.