'Silent' antibiotic resistance genes: an overlooked issue of considerable importance in antibacterial chemotherapy?

点击翻译按钮获取中文摘要

Antibiotics enable the treatment and cure of life-threatening bacterial infections, and represent one of the great successes of modern medicine. Unfortunately, the utility of these agents is being progressively eroded as bacteria evolve to resist their effects, and antibiotic resistance is now considered one of the three greatest threats to human health. A key aspect of dealing with antibiotic resistance effectively in medical practice is strategic intelligence. Being in possession of up to date information about the proportion of bacterial strains in a given location that are resistant to particular antibiotics allows doctors to decide which would be the best antibiotics to use routinely to treat bacterial infection, and to avoid those which are probably not going to work because resistance is so commonplace. In the case of a life-threatening bacterial infection, knowing precisely which antibiotics the specific bacterium present in the patient is resistant or susceptible to enables the doctor to select the best antibiotic treatment to cure the patient.This project is focussed on investigating a phenomenon that may be seriously undermining our strategic intelligence regarding antibiotic resistance. Recent work in the applicant's laboratory has established that some bacteria that are sensitive to antibiotics nonetheless carry genes that are normally associated with antibiotic resistance, but that these genes have become switched off ('silenced'). This phenomenon, which we have termed 'silencing of antibiotic resistance by mutation' (SARM) is of considerable concern, as bacteria with SARM would appear susceptible to an antibiotic when tested, but could then very quickly and easily become resistant to the antibiotic during treatment in a patient. Currently, we do not know how widespread SARM is amongst bacteria that cause disease, nor do we understand properly how SARM occurs. The present proposal aims to investigate both of these issues in the so-called 'superbug', Staphylococcus aureus.To establish how common SARM is, a large collection of 1500 S. aureus isolates recovered from patients around the world will be tested. Each strain will undergo DNA sequencing of its genome to establish its complete genetic make-up, which will allow for the identification of genes that are known to be associated with antibiotic resistance. In addition, the susceptibility of each isolate to a wide range of commonly used antibiotics will be established to determine if the bacterium displays resistance to all the drugs that it has the genetic potential to display resistance to. Strains that carry antibiotic resistance genes, but do not exhibit resistance to the corresponding antibiotics, represent potential SARM strains. These strains will be studied in detail to establish how easily they can switch their 'silenced' resistance genes back on, and to understand the mechanism(s) by which SARM works.