There has been much recent talk about how to target the rising tide of antibiotic resistance across the world, one of the biggest threats to global health today.
While there is no doubting the size of the problem facing scientists, healthcare professionals and the pharmaceutical industry, there are innovative ways we can target antibiotic resistance in the short term, which are discussed in three articles published in Essays in Biochemistry.
With only a few antibiotics in development and a long drug development process (often 10-15 years), there is concern that what is being done to combat antibiotic resistance may be 'too little, too late'.
"If bacteria continue developing resistance to multiple antibiotics at the present rate, at the same time as the antibiotic pipeline continues to dry up, there could be catastrophic costs to healthcare and society globally," said senior co-author on one of the articles, Dr Tony Velkov, an Australian National Health and Medical Research Council (NHMRC) Career Development Fellow from Monash University, Victoria, Australia.
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 (eg, 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 that pose the greatest threat to human health that was just 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 another paper in the same issue written by the Guest Editor of the journal, Dr Rietie Venter, University of South Australia, Adelaide, and 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 non-antibiotics. Using this novel approach, an FDA-approved non-antibiotic drug is combined with a specific antibiotic that enables it to breach the outer membrane barrier and so restore the activity of an antibiotic. The Monash University authors discuss how combining antibiotics with other non-antibiotic drugs or compounds can boost their effectiveness against Gram-negative 'superbugs'.
For example, loperamide, an anti-diarrheal 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 multi-drug resistant Pseudomonas aeruginosa, a causative agent in hospital-acquired infections such as ventilator-associated pneumonia.
Polymyxins are a type of antibiotics that target Gram-negative bacterial infections and have traditionally been used as a last resort to treat serious infections such as those caused by Gram-negative 'superbugs' Klebsiella pneumoniae, P. aeruginosa and Acinetobacter baumannii. Resistance to polymyxins is not common, but in late 2015 the first transferable resistance gene to colistin (polymyxin E) was discovered (plasmid-borne mcr-1 gene). This caused significant concerns, as once resistance to polymyxins is established, often no other treatments are available.
A number of researchers, including the team based at Monash University, have been testing different combinations of drugs or compounds with polymyxins to try and improve their effectiveness against these bacterial 'superbugs'.
"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." commented senior co-author on the paper, Professor Jian Li, Head of the Laboratory of Antimicrobial Systems Pharmacology from Monash University, Victoria, Australia.
Some interesting findings have ensued, with a number of different combinations having a beneficial effect. Some notable examples that increased antibiotic activity when combined with polymyxin B include: ivacaftor and lumacaftor, two new 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), according to Schneider and co-authors, is combining the antibiotics ampicillin or oxacillin with berberine. Berberine is extracted from the roots, stems and bark of plants such as barberry.
In addition to the above, 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, discovered by using an 'iChip' to culture and isolate soil bacteria in situ.