Understanding mechanisms of antimicrobial resistance (AMR) in Streptococcus pneumoniae clinical isolates

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The bacterium Streptococcus pneumoniae, also called pneumo, causes invasive diseases such as: pneumonia and meningitis, which lead to millions of deaths every year. To prevent and treat pneumo infections in hospitals and clinics, patients are given penicillin antibiotics, or drugs very similar to them. These drugs kill the bacteria growing inside the patient, combating the infection and curing the individual. Increasingly, strains resistant to penicillin are emerging across the world threatening our treatment strategies and jeopardising patient outcomes. Therefore, there is an urgent need to address penicillin resistance in pneumo to prevent patient deaths. This project will identify and characterise the biological underpinnings of resistance and aims to find way of re-sensitising strains to antibiotics we routinely use in clinics.To address, and ultimately prevent, penicillin resistance in pneumo we need to understand how resistance occurs in the first place. This understanding is vital to end an all too familiar pattern of: a new drug discovery leading to resistant bacteria, resulting in a search for yet more drugs.Penicillin resistance in pneumo does not occur in a single step, but emerges gradually as the bacterium acquires genetic alterations one at a time. Using pneumo strains isolated from patients, we have discovered a strain that is emerging on its journey towards antibiotic resistance and therefore contains a limited number of genetic changes. This strain is typical of the pattern of pneumo penicillin resistance in hospitals in the UK and already shows 'low-level' resistance to this drug. Importantly, strains of the same type are responsible for pneumo infections across the globe. Therefore cellular processes we discover in this study will be generally applicable to worldwide bacterial lineages (families of related strains). In preliminary work, we have already identified some of the genetic changes in this stain by genome sequencing, but we do not know which of these changes are important for underpinning the penicillin resistance. Our hypothesis is that one, or more, of these genetic changes is responsible for the 'low-level' resistance in this strain and these changes are an important step towards 'high-level' penicillin resistance in pneumo strains.To test our hypothesis, we will carry out three parallel identification methods all powered by next-generation DNA sequencing: a whole genome profiling method (Tn-Seq) and two related whole-genome sequencing methods. These methods will identify the factors that are important for the strains to resist penicillin treatment and, once identified, we will carry out further work to understand how these new factors function. Importantly, our preliminary work has already identified a new resistance determinant and we will carry out experiments to understand its function in the pneumo cell. Our primary aim is to re-sensitise the 'low-level' penicillin resistant clinical isolate to penicillin treatment and we will test our new understanding of resistance in a model infection system, which mimics treatment of patients in clinic. This research will help us tackle the global threat of antibiotic resistant infections, by finding ways to make sure drugs work properly when given to patients with deadly S. pneumoniae diseases.