According to the World Health Organization (WHO), the rapid surge of bacterial resistance to antibiotics is considered to be one of the most serious and widespread threats to public health. Antibiotics are one of the pillars of modern medicine but sooner than expected the world is headed for a post-antibiotic era, the implications of which would be devastating.
“The average lifespan at the turn of the 19th century was about 45 years of age and that has almost doubled today,” says Dr. Grant Pierce, Professor of physiology and pharmacy at the University of Manitoba and Executive Director of Research at St. Boniface Hospital. “While numerous factors play a role, the primary reason is the advent of antibiotics. If all antibiotics are going to be ineffective by 2030, as predicted by rates of multi-drug resistance, this is going to be a major problem.”
Statistics from WHO show that approximately 480,000 people develop multi-drug resistant tuberculosis each year, and drug resistance is starting to complicate treatment of serious ailments such as HIV, influenza and malaria.
Until recently, the majority of antibiotics have addressed the same three targets: protein synthesis, DNA replication and bacterial cell wall assembly. “There wasn’t an urgent need to develop new classes or pursue alternative targets,” says Pierce, “but this is no longer the case.”
Molecules that inhibit non-traditional bacterial targets represent an attractive alternative and this is precisely what researchers at the University of Manitoba and St. Boniface Hospital in Winnipeg aimed to accomplish. They have developed the first new class of antibiotics that target bacterial energetics with proven activity against drug-resistant pathogenic bacteria such as Chlamydia trachomatis.
According to the study, a number of bacterial pathogens override sodium-ion circulation (Na+) in mammalian cells and use it as a direct source of energy. Inhibition of the primary bacterial Na+ pump, termed NQR, would remove the bacteria’s power supply ultimately halting growth and the infection process.
Inspiration came from the naturally occurring antibiotic, korormicin, which was isolated from marine bacterium in 1997. To date, korormicin is the best known NQR inhibitor and experiments on cells infected with Chlamydia trachomatis demonstrated the critical importance of NQR in the growth and proliferation of these strains of pathogenic bacteria. Although promising, korormicin displayed high toxicity at low concentrations which prevents it from ever advancing to clinical trials.
This setback however, encouraged a new design. The next generation molecule, PEG-2S, is more suitable as an anti-NQR medicine as the toxic effects are minimized and its activity against Chlamydia trachomatis enhanced, resulting in even higher potency relative to korormicin.
A pivotal advantage of PEG-2S is its potentially high selectivity as NQR is present in only a select number of pathogenic bacteria. This means that healthy cells, as well as beneficial bacteria already present in our body, would be unaffected by the PEG-2S antibiotic.
“Due to their normal mode of action, current antibiotics will wipe out beneficial gut bacteria which allows for opportunistic bacteria to come in and take over. Since NQR is only present in pathogenic bacteria, we don’t see this side effect from PEG-2S, which is wonderful.”
Pierce also adds, “We think that because of the mechanism we’re targeting, this [new class of antibiotic] may help in situations where traditional antibiotics are no longer effective. This obviously depends on the target and on future results but we are thinking this could be a first line treatment for infections for which there is currently limited treatment.”
Indeed, the data indicates that PEG-2S and subsequent derivatives will have activity beyond the inhibition of chlamydial pathogens.
The results are positive and very promising however there are still many hurdles to overcome. First, the structure of PEG-2S must be optimized followed by an activity screen against the long list of NQR-containing bacterial targets. Then, testing must be moved from cell lines to animal models and eventually, human trials.
The timeline is still unclear but Pierce expects things to move quickly as various governing bodies have recognized the impeding threat of antibiotic resistant bacteria and have mandated that molecules such as PEG-2S be given priority and fast tracked through to clinic trials.
