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Towards a global approach to combat antibiotic resistance

The eradication of infectious diseases in the 20th century is arguably one of the most important achievements in modern medicine. The treatment of such illnesses as tuberculosis, leprosy, syphilis, cholera, pertussis, or diphtheria with antibiotics – substances specifically targeting the bacteria causing them – have reduced suffering, increased hygiene, enormously improved lifestyle, and skyrocketed life expectancy around the globe – particularly in developed countries.

Less than a century onwards, these advancements are seriously at risk. Paradoxically, this is caused by the use of antibiotics itself.

From a biological point of view, this phenomenon is easy to explain and already envisaged by Alexander Fleming, the discoverer of penicillin, the first antimicrobial ever. Antibiotics are naturally produced by microorganisms living in niches with high microbial diversity, like soil, to kill competitors. By inhibiting neighbouring cells, antibiotic producers gain a competitive advantage and enjoy more resources for themselves – food, space, or both.

In general terms there are three ways by which bacteria acquire resistance toward an antibiotic: They can block its entry into the cells (or enhance its exit), they can inactivate or degrade it, or they can alter its target so that the antibiotic can no longer exert its action.

When resistance toward antibiotics is not innate, as it is the case for our own body cells, antibiotic production and antibiotic resistance is an evolutionary arm-wrestle, and its playground is DNA. By accumulating mutations in their DNA, bacteria can for example modify the structure of a cell component targeted by an antibiotic. Upon selective pressure – i.e. presence of the drug – only the cells with the mutations in their DNA are positively selected and can further multiply. Moreover, bacteria can easily exchange DNA, meaning that a resistance can spread within a population or even between different species.

Since the last 20 years, no new antimicrobial has been discovered and, in parallel, resistance toward all major classes of antibiotics has been reported. This has been fostered by the massive, and occasionally wrong, use of antibiotics in medicine and agriculture. Multidrug-resistant strains, against which no antibiotic exerts its function any longer, have emerged.

As outlined in a recent commentary by FEMS President Jean-Claude Piffaretti, a study published in The Lancet Infectious Diseases addresses resistance of enterobacteria like Escherichia coli toward colistin (polymyxin E), a so-called “last-resort” drug. The drug disrupts the membrane of Gram-negative bacteria and is therapeutically important to treat enterobacteria resistant to most antibiotics. Resistance toward colistin has been previously reported, but the responsible DNA mutations conferred a fitness disadvantage for the cell and were localized in the chromosome (the main carrier of the genetic information). Thus, the resistance did not spread easily within a population of bacteria.

Continuous efforts in basic research are equally crucial … The quest for new natural substances with novel modes of action is also ongoing.

The authors of the study monitored resistance toward colistin in enterobacteria from intensive pig farms in China over the last years. Intensive husbandries often rely on the extensive use of antibiotic to foster animal growth and health. The authors observed an increase in the number of bacteria resistant to the drug, and argued that this is due to exchange of genetic material other than chromosomal DNA. Subsequent molecular analyses verified that the resistance determinant is located on a plasmid – a small, circular fragment of DNA that can be easily transferred from cell to cell.

The researchers found that the gene responsible for colistin resistance, called mcr-1, encodes for a protein (MCR-1) which alters the membrane of the bacteria and makes them insensitive to the drug. The plasmid carrying the gene can be exchanged between bacteria of the same species (conjugation) and also be transferred to other species (transformation), eventually resulting in its broad dissemination. Indeed, the authors were able to identify the mcr-1 gene not only in about 21% of E. coli obtained from livestock but also in a high number of bacteria isolated from retail pork and chicken meat (about 15%) as well as in 1% of hospital patients infected with E. coli and another enterobacterium, Klebsiella pneumoniae, indicating an animal-to-man transmission.

These findings are worrisome insofar the effectiveness of the last-resort drug colistin is put at risk. Currently, Asian countries including China are the major producers and consumers of the antibiotic, mainly for agricultural purpose. In this sense, the study by Liu et al. is both a cautionary note and an exhortation for a global action to fight antibiotic resistance. Beside the effective communication to the public to raise awareness and the proper prescription and use of antibiotics as therapeutics, an integrative approach to unite human and veterinary medicine as well as agricultural practices is sought after. This approach is proposed by the One Health Initiative and supported among others by the FEMS (Federation of European Microbiological Societies).

Continuous efforts in basic research are equally crucial. New strategies targeting the social life of bacteria instead of single cells are currently investigated to tackle the issue of antibiotic resistance. The quest for new natural substances with novel modes of action is also ongoing. Recently, an innovative approach has been used to identify a previously unknown antibiotic substance without detectable resistance. From a microbiological perspective, it is baffling that the overwhelming majority of microbes is unknown or doesn’t grow in the laboratory. On top of this, “cultivable” microbes have a metabolism which is mostly silent under laboratory conditions. It is this so-called “secondary metabolism” that microorganisms activate in nature to produce antibiotics – indicating that a wealth of new natural drugs is still untapped.

If and when such new approaches or novel drugs will effectively halt the spread of antibiotic resistance still remains to be seen. In the meanwhile, a concerted action as proposed by the One Health Initiative is even more crucial.

Featured image credit: “Fall Coloured Pills” by Martin Cathrae. CC BY SA 2.0 via Flickr.  

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