Multidrug Resistance

Multidrug Resistance

Arthur Neuberger explains how increasing antibiotic resistance is a global threat that we breed inside ourselves

In an interview with the BBC on the emerging threat of antibiotic resistance, Professor Dame Sally Davies, the Chief Medical Officer for England, made clear that if global society does not take countermeasures against the spread of antibiotic resistance today, in 10 to 20 years from now, we all might be back to an 19th century scenario. In such a situation even basic infections as a result of routine operations would almost certainly be lethal, not to mention the inability to conduct most of our current cancer treatments. The World Health Organization ranks multidrug resistance (MDR) as one of the three greatest risks to human health, the others being climate change and malnutrition.

Scientists have discovered bacterial antibiotic resistance genes in DNA extracted from 30,000 year old permafrost sediments in Bear Creek, Canada, showing that drug resistance is certainly not just a recent evolutionary trend. By analysing these genes, they have demonstrated the striking similarity between current bacterial drug resistance genes and those of 30,000 years ago. What is new, however, is the increasing spread of multidrug resistant strains that are able to withstand specific antibiotics as well as complex cocktails. One major factor driving the increasing emergence of these multi-resistant organisms is the excessive application of antibiotics in medicine and farming, resulting in continuous exposure to antibiotics in these environments.

The rapid emergence of multidrug resistant bacterial strains represents a serious ethical issue for the global community. Ineffective treatment does not just affect the patient, but has wider implications for the population. Worldwide, the evolution of drug resistance is the result of simultaneous over-consumption or incorrect use (such as a failure to finish the full course) of antibiotics by wealthy nations, and underconsumption by developing countries. In the latter, dangerous strains are rarely treated correctly due to the lack of medicines and treatment, and are therefore never fully eradicated. The same pathogenic strains can then be further selected for hyper-multidrug resistance in an environment like a patient’s intestine, which is exposed to multiple antibiotics in a typical Western hospital. This interconnectivity means that health, especially in the context of MDR and infectious diseases, should be treated as a global public health concern, not just a national one. When microbes develop resistance in one patient because of over- or underconsumption of medication, this more dangerous malady poses an increased risk to others.

“Ineffective treatment does not just affect the patient, but has wider implications for the population”

Compounding this, many international pharmaceutical companies have abandoned the development of new antibiotics. The rapid global spread of antibiotic resistance, which has significantly reduced the time span during which antibiotics are effective, together with the low prices of antibiotics have made return of investment problematic for many companies. A study by the Cambridge Judge Business School, examining the success drivers of the pharmaceutical industry, further confirmed that the antibiotic pipelines dried up some time ago. Even though new attempts to develop antibiotics and blocking agents of multidrug resistance have restarted recently, real progress is difficult due to a lack in our detailed understanding of the mechanisms by which drug resistance develops. In a development process aimed at launching sustainable drugs on the market, basic research on the evolution, spread and mechanisms of MDR is needed, more than ever, in order to overcome these roadblocks. This research can reveal surprising new insights that might become important therapeutically in the future.

There are various mechanisms by which bacteria can survive under, and eventually adapt to, antibiotic exposure. Even non-mutated—or ‘wildtype’—strains have a basic set of countermeasures to antibiotic stress. Drug efflux pumps are a good example. These are molecular structures (proteins) embedded in the plasma membrane of the cell, which can recognise and expel a vast range antibiotics from the cell before these drugs can do significant harm to the interior. Scientists in the van Veen group (Department of Pharmacology, University of Cambridge) believe that, in the first instance, these pumps allow wild-type strains to cope with increased amounts and complex cocktails of antibiotics. Studies have shown that the same strains suddenly become hypersensitive to drugs once the genes that encode these pumps are knocked-out. Other important mechanisms of antibiotic resistance act directly on the antibiotic through modification or degradation by enzymes.

Existing mechanisms can be improved through genetic mutations; errors in DNA replication during cell division. Some of these errors can be beneficial for survival under certain conditions. For instance, a gene coding for an antibioticdestroying enzyme could mutate in such a way that it can now recognise and degrade members of other chemical families. Alternatively, a mutation could cause a genetic variation of the drug target itself (for example, a protein or piece of nucleic acid to which the drug binds and therewith blocks this molecule’s further actions and usage). These variations decrease the drug’s capability to interact with these targets, thus reducing the effectiveness of the drug as an inhibitory agent. Drug resistance can also be acquired through the expression of an alternative target in the cell that interacts less well with the antibiotic.

Eventually, in the course of cell division, these resistance-associated genes are inherited by daughter cells and can also be forwarded to less resistant kinsmen, from either the same or other species, via genetic exchange. In the latter process, multidrug resistance-causing genes are copied onto a mobile DNA-carrier and via this, transferred by their donor to an acceptor bacterial cell. In other cases, bacterial viruses transmit resistance genes in the process of infections. As far as such interactions in bacterial communities are concerned, Lee and colleagues have shown that bacteria can be true altruists when it comes to dealing with antibiotic stress. They can secrete signalling molecules to help not-yet resistant cells deal with antibiotic toxicity, despite this having no obvious value for themselves.

Today, various research groups study different aspects of multidrug resistance worldwide; here in Cambridge, for example, the van Veen group are carrying out functional and structural studies of efflux pumps. We need a broad-stroke understanding of the mechanisms of MDR emergence and spread, both on a molecular level and in the context of global health care systems (detective, preventive, and corrective regulations and actions). Practitioners, policy makers and scientists are therefore invited to collaborate and engage in multidisciplinary, integrative research and decision-making, with the aim of combating one of the biggest threats that our society faces today.

Image credit: NIAID