News and Opinions  –  2017

Resistance to last-line antibiotics

2017-06-30

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.

Polymyxins

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

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.

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