Meeting the Challenge of Antibiotic Resistance

Scientists work on innovative strategies

Antibiotic-resistant bacteria remain one of the biggest threats to global health. With only a few antibiotics in development and a long drug-development process (often 10 to 15 years), there is concern that what is being done to combat antibiotic resistance may be “too little, too late.” Three articles published in Essays in Biochemistry discuss ways that antibiotic resistance may be targeted in the short term.

While any antimicrobial resistance is concerning, the increasing incidence of antibiotic-resistant gram-negative bacteria has become a particular problem as strains resistant to multiple antibiotics are becoming common, and no new drugs to treat these infections (e.g., carbapenem-resistant Enterobacteriaceae) will be available in the near future. These gram-negative bacteria are considered the most critical priority in the list of the 12 families of bacteria posing the greatest threat to human health that was recently released by the World Health Organization.

The reasons for the high levels of antimicrobial resistance observed in these critical gram-negative organisms are explained in a paper by Dr. Rietie Venter of the University of South Australia, Adelaide, and his colleagues. According to the authors, one of the main contributing factors to the increased resistance observed in gram-negative bacteria is the permeability barrier caused by their additional outer membrane.

An innovative strategy that is gaining momentum is the synergistic use of antibiotics with FDA-approved nonantibiotics, the paper says. Using this new approach, an FDA-approved nonantibiotic drug is combined with a specific antibiotic that enables it to breach the outer membrane barrier, thereby restoring the antibiotic’s activity. The authors discuss how combining antibiotics with other nonantibiotic drugs or compounds can boost their effectiveness against gram-negative “superbugs.”

For example, loperamide, an antidiarrheal medication sold in most pharmacies, enhances the effectiveness of eight different antibiotics (all in the tetracycline class). In particular, when added to the tetracycline antibiotic minocycline, along with the Parkinson’s disease drug benserazide, it significantly increased antibiotic activity against multidrug- resistant Pseudomonas aeruginosa, a causative agent in hospital-acquired infections, such as ventilator-associated pneumonia.

Polymyxins, which target gram-negative bacterial infections, have traditionally been used as a last resort to treat serious infections, such as those caused by gram-negative Klebsiella pneumoniae, P. aeruginosa, or Acinetobacter baumannii. Resistance to polymyxins is not common, but in late 2015 the first transferable resistance gene to colistin (polymyxin E) was discovered. This caused significant concerns, as once resistance to polymyxins has been established, often no other treatments are available.

A number of researchers, including a team at Australia’s Monash University, have been testing different combinations of drugs or compounds with polymyxins to try and improve their effectiveness against these “superbugs,” according to another paper in the same issue of Essays in Biochemistry.

“Without new antibiotics in the near future, we must explore innovative approaches to preserve the clinical utility of important last-line antibiotics, such as the polymyxins,” said senior coauthor Professor Jian Li.

Some notable examples that increased antibiotic activity when combined with polymyxin B include ivacaftor and lumacaftor, two drugs used to treat cystic fibrosis; and closantel, a drug used to treat parasitic worm infections.

Another interesting combination that has shown promise against methicillin-resistant Staphylococcus aureus (MRSA) is combining the antibiotics ampicillin or oxacillin with berberine. Berberine is extracted from the roots, stems, and bark of plants, such as barberry.

In the third paper, Dr. Mark Blaskovich and colleagues at the University of Queensland in Brisbane, Australia, describe the key ways they believe antimicrobial resistance can be targeted.

“In the short term, the greatest potential for reducing further development of antimicrobial resistance lies in developing a rapid test that can quickly tell whether or not you have a bacterial infection (as opposed to a viral cold or flu), and whether you really need an antibiotic,” Blaskovich said. “Even better if the test could say what type of bacteria and what types of antibiotics it is resistant to. You could then treat an infection immediately with the appropriate antibiotic, rather than the trial-and-error method now used. These tests could be ready within the next five years, and would have a huge impact on reducing unnecessary antibiotic use, preserving our existing antibiotics and reducing the spread of antibiotic resistance.”

Regarding antibiotics in particular, Blaskovich and his colleagues describe a number of possible strategies to pursue. The first is to improve existing antibiotics. For example, the authors recently created a modified version of vancomycin to increase its potency and to reduce its toxic effects.

Another option is to rediscover old antibiotics. In the 1950s and 60s, many potential antibiotic drugs were described in the scientific literature, but because so many choices were available at the time, only some were developed for human use. An example of this is the octapeptins, which are newly rediscovered antibiotics that are now being developed to combat gram-negative pathogens.

Repurposing drugs originally developed and approved for other uses has also had some success. In 2005, the Drugs for Neglected Diseases initiative identified fexinadole as a potential treatment for sleeping sickness, and it is now being studied in a phase 3 trial. This drug had been developed as an antimicrobial in the 1970s, but only reached preclinical development.

In addition, researchers are looking for new, untested sources of antimicrobial activity to try and develop new drugs. A recent success in this area was teixobactin, a new antibiotic developed by NovoBiotic Pharmaceuticals. The drug was discovered by using an “iChip” to culture and isolate soil bacteria in situ.

The final option mentioned by Blaskovich and colleagues is crowd-sourcing new antibiotics. Using this approach, the Community for Open Antimicrobial Drug Discovery is searching compounds sourced from academic chemists around the world.

“It’s hard to predict which one of these methods will be the most successful in the future, but we really need to be trying all of them to have any chance of overcoming antibiotic resistance,” Blaskovich said.

“Nonantibiotic strategies are just as important, such as developing vaccines or probiotic therapies to prevent infections, as they can help to reduce the overuse of antibiotics,” he added. “They will never completely replace antibiotics but can help to preserve our existing antibiotics so they still work when needed.”

Source: EurekAlert; March 3, 2017.