Public Health Emergency - Leading a Nation Prepared
Author: Brian N. Tse, Ph.D., Health Scientist, Antibacterials Branch, Division of Chemical, Biological, Radiological, & Nuclear Medical Countermeasures, Biomedical Advanced Research & Development Authority (BARDA), HHS Office of the Assistant Secretary for Preparedness & Response Published Date: 6/7/2016 3:53:00 PM
Category: Innovations; Medical Countermeasures; Public Health Preparedness;
For the first time, the bacterial gene mcr-1, which confers resistance to the “antibiotic of last resort,” colistin, was found in a bacterium isolated from a patient in the United States. The bacterium bearing the gene, a member of the E. coli strain, was recently found in the urine sample of a woman in Pennsylvania. While this particular strain of bacteria is still sensitive to other antibiotics, there is concern that its appearance in the U.S. may signal the dreaded arrival of readily-transferrable colistin-resistance to the American healthcare system.
Resistance to colistin, a member of the polymyxin-class of antibiotics, is especially troubling because colistin is widely considered the drug of last resort for treating patients with multidrug-resistant infections. Amongst multidrug-resistant bacterial strains, one particularly dangerous family of bacteria is the carbapenem-resistant Enterobacteriaceae (CRE).
The medical community is particularly concerned about CRE given that nearly half of all hospital patients that contract CRE-based bloodstream infections do not survive.
Colistin, one of the few antibiotics left that still works against CRE, often serves as the last available treatment option for those fighting these deadly infections. Given the lack of alternatives, the rapid spread of resistance to this last line of defense is cause for alarm.
The mcr-1 gene is one that that confers colistin resistance to its bacterial carriers. While its appearance in the U.S. is certainly distressing, it is not altogether surprising. Scientists first identified the mcr-1 gene in China in 2015 and since then have found it lurking in bacteria in other locations around the world. The gene itself is found on a small piece of DNA called a plasmid that is capable of moving from one bacterium to another.
As such, the mcr-1 containing plasmid can help spread of colistin resistance rapidly to other bacteria, including those already resistant to all other available antibiotics. As a result, a ‘post-antibiotic era’ of deadly bacterial strains that are not treatable with any available antibiotic is becoming a very real possibility – a potentially nightmarish scenario for healthcare providers.
Having recognized that drug-resistant bacteria are a serious health threat, and in particular, CRE strains that are resistant to the last remaining treatments (in other words, colistin), BARDA already has made investments to develop new antibiotics that will bolster the treatment options. One such candidate is plazomicin, a product under development in partnership with Achaogen, Inc.
Plazomicin is a novel member of the aminoglycoside class of antibiotics, a group that includes such well-known antibiotics as gentamicin and amikacin. However, unlike its predecessors, plazomicin has been engineered to overcome the resistance mechanisms that bacteria use to inactivate other aminoglycosides. Plazomicin is active against a broad spectrum of bacteria, including multidrug-resistant strains that are not susceptible to many other antibiotics.
Of note, plazomicin shows activity against bacterial isolates that exhibit both carbapenem- and colistin-resistance, making it a candidate for treating CRE infections or infections resulting from colistin-resistant strains. In one exciting set of preliminary laboratory tests, plazomicin demonstrated activity against colistin-resistant strains that use the same mechanism of resistance as that conferred by the mcr-1 gene.
Plazomicin currently is being tested in two Phase 3 clinical trials, one focusing on the treatment of patients with serious infections due to CRE, and the other focusing on the treatment of patients with complicated urinary tract infections (cUTI).
As a continuation of this project, BARDA recently awarded an option worth $20 million on its current contract with Achaogen to fund, in part, the cUTI Phase 3 clinical trial. This clinical trial is intended to support the FDA approval of plazomicin, thereby bringing it to the market for clinical use.
Other promising candidates are being developed through BARDA’s public-private partnership with GlaxoSmithKline, plc (GSK). This partnership enables BARDA and GSK to develop, jointly, a flexible collection of drug candidates identified from GSK’s own antibiotic portfolio.
One is gepotidacin (GSK2140944), the first in a new class of antibiotics that is currently in Phase 2 human clinical trials for the treatment of gonorrhea. Gepotidacin is a novel triazaacenapthylene antibacterial that selectively inhibits bacterial DNA gyrase and topoisomerase IV by a unique mechanism not utilized by any currently approved human therapeutic agent.
A second candidate is a compound called GSK3342830, a novel cephem antibiotic that is engineered to take advantage of bacterial iron-uptake pathways, thereby increasing its own uptake into (and therefore, activity against) otherwise drug-resistant bacteria.
Both candidates show broad-spectrum in vitro activity against a variety of multidrug resistant bacterial strains, including colistin-resistant E. coli strains specifically bearing the mcr-1 plasmid (limited set of data). Although more tests will be necessary to explore the potential of both drugs for treating colistin-resistant bacterial infections in the clinic, these preliminary results are very promising.
These three compounds – plazomicin, gepotidacin, and GSK3342830 – represent components of BARDA’s existing antibacterials portfolio that have the potential to address colistin-resistant strains, a critical gap in our current medical armamentarium.
As new forms of antibiotic resistance continue to spread globally, the possibility for nightmarish bacterial strains can no longer be ignored; the continued development of new options for treating drug-resistant bacteria will be essential to preserving our ability to effectively combat infections. BARDA and its industry partners will continue to lead the charge against these threats, both present and future.
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