The increasing resistance to antibiotics and lack of antibiotics with new mechanisms of action against Gram-negative bacteria has caused the revival of old, formerly abandoned, drugs as last options. The first ones to regain popularity were the polymyxins, colistin and polymyxin B. Developed in the 1950s, the polymyxins fell out of favor due to toxic adverse effects such as kidney damage and affecting the nervous system. Current, more pure, formulations coupled with better understanding of their pharmacology have made the adverse reactions more rare and manageable.
The next drug to make a comeback was fosfomycin, which was developed in the 1960s and was widely used against urinary tract infections. However, it is not suitable for long-term treatment due to resistance development during therapy. Today it is used as an effective treatment option against bacteria carrying Extended Spectrum Beta-lactamases (ESBLs).
ESBL – Extended spectrum beta-lactamase, an enzyme that destroys most beta-lactam antibiotics such as penicillins and cephalosporins. Many variants are identified, e.g. the CTX-M, and TEM groups. ESBLs do not necessarily have activity against carbapenems, although e.g. KPC and NDM-1 do.
Many have hoped that these drugs would be lifesavers and help bridge the gap between the drought in the antibiotic research pipeline and rapidly increasing antibiotic resistance. Unfortunately evidence, with new reports of emerging and spreading resistance, indicates that these drugs may not after all be sufficient.
The polymyxins act by interfering with the cell membranes of bacteria. They bind to the phospholipids in the membranes and break them apart. As a result, cell contents leak out and the bacteria die. Although some bacteria have been known to be able to modify their membranes so that the polymyxins no longer bind to the membrane, the occurrence has been low and most have turned out less viable.
However, researchers recently discovered a new gene, mcr-1, which causes similar changes in the membranes without significantly affecting viability or virulence. The gene was found on a plasmid, a mobile genetic element, making it transferrable between different strains and even species of bacteria. Since the discovery was published in 2015, researchers have searched for the gene in a variety of samples. Several variants of it have also been identified since, the latest one published in June 2017. Mcr genes have been found all over the world in the environment, animals and humans – even causing disease in patients.
mcr-1 – Mobilized Colistin Resistance, a gene that is found on a plasmid and encodes a phosphatidylethanolamine transferase, an enzyme that modifies the lipid A portion of the outer membrane/LPS, causing the polymyxins to not bind to the membrane. At least six variants of mcr-1 and two closely related versions, mcr-2 and mcr-3 have been identified.
The global spread of the genes and the fact that it has been found in samples taken already in the 1980s suggest that the gene has been around for some time, and that the increased use of polymyxins has enabled it to spread even more.
Fosfomycin in turn acts by inhibiting the formation of the bacterial cell wall. More specifically, it inhibits an enzyme called MurA, which produces the substance that binds together the peptide and glycan parts of the cell wall. However, fosfomycin is dependent on a transporter in the bacterial membrane to get inside the bacteria. This transporter is not essential to the bacteria, and can in some cases be deactivated, causing therapeutic failure.
Additionally, a few enzymes are known to be able to dismantle and inactivate fosfomycin. Genes for all of these have been found on both plasmids and in chromosomes, making them potential threats to the efficacy of fosfomycin. In a recent paper from 2017, researchers in Canada discovered a new variety of these, fosA7, in Salmonella from broiler chicken. Given that undercooked or mishandled broiler meat is a significant source for salmonella infections, it is probably only a matter of time before fosfomycin-resistant bacteria are found in humans. Moreover, if the resistance genes are found on a suitable plasmid, the genes will start spreading between species.
fosA –Fosfomycin contains a reactive moiety, an epoxide ring, which effectively incapacitates MurA. The gene fosA encodes the enzyme FosA which, along with the related FosB and FosX, opens up the epoxide ring, rendering fosfomycin ineffective. FosC, also causing fosfomycin resistance, modifies fosfomycin so that it can no longer react with the target enzyme.
Save our antibiotics!
The reports of increasing resistance to the antibiotics that we now rely on when nothing else works are extremely worrying. When the polymyxins and fosfomycin were pulled out from the figurative dusty cupboards of times past, hopes were that these would help us manage the silent tsunami of antibiotic resistance until new antibiotics are developed. But in spite of increased awareness and political attention the situation and efforts to boost antibiotic drug discovery, results and sustainable solutions are still lacking.
Urgent attention needs to be directed towards improving surveillance of resistance development, antibiotic stewardship and wise use of antibiotics, both within human and animal medicine in all countries. The model for research and development of new antibiotics needs urgent modification by delinking the cost of R&D from the end product price and volume of sales to ensure affordable access. And finally, a major step is also to completely ban the use of antibiotics – especially our last-line defenses – for routine use and as growth promoters in food production.
Understand bacteria in the ReAct Toolbox
Bacteria are found all around us; in the air we breathe, in the soil and water, even inside and on our bodies. They are tiny single-celled organisms, only a few micrometers in size, and the individual cells can only be seen under a microscope. Read more in the ReAct Toolbox.
More from "2017"
- Food, microbes and health
- ReAct’s priorities in what promises to be an important autumn for antibiotic resistance
- Many countries identify antimicrobial resistance as an obstacle on their way to implementing Agenda 2030
- Important African conference: How will we be able implement National Action Plans on Antimicrobial Resistance?
- Antibiotic resistance: national workshop in India for voluntary organizations
- Resistance to last-line antibiotics
- Essential Diagnostics List (EDL) to be developed
- Media workshop in Ecuador: a success
- ReAct withdraws from IMI project DRIVE-AB
- Microbes – friend, foe or both?
- ReAct Asia Pacific hosts workshop on antimicrobial resistance in the farm sector
- Successful antimicrobial resistance media training in Nairobi, Kenya
- Mother Earth, One Health – International Encounter in Argentina
- Key take-aways from the World Health Assembly 2017 on antimicrobial resistance
- National action plans and global AMR framework on the agenda as 70th World Health Assembly kicks off next week
- ReAct co-hosts side event during World Health Assembly
- ReAct supports countries in the development of National Action Plans on AMR
- Lack of access to old antibiotics drives antibiotic resistance development and impairs patient outcomes
- Hand hygiene saves lives
- The Swedish Government awards Reward Medal to Professor Otto Cars
- Presentation of the Alforja Educativa Validation Project enthuses students
- New antibiotics in the news
- Free online course: Antibiotic Resistance: the Silent Tsunami
- Tell Our Bac-Stories!
- India’s link between tuberculosis and antibiotic resistance
- Environmental effects of antibiotics in sewage
- Professor Larsson on India’s National Action Plan on AMR and emissions from antibiotics production
- India’s new National Action Plan on Antimicrobial Resistance
- Professor Otto Cars to serve as Expert in UN Inter-Agency Coordination Group on Antimicrobial Resistance
- Johns Hopkins Bloomberg School of Public Health is looking for a Research Associate
- Could the use of Antimicrobial Peptides create resistance to ourselves?
- Boston Consulting Group report shies away from addressing affordable access and stewardship
- WHO Releases Priority Pathogens List
- Antibiotic Smart Use project nominated for global UN Award
- European Commission diagnostic prize winner announced
- Recap of WHO 140th Executive Board meeting
- New collaboration on strategies for tackling antibiotic resistance