BioProject

Antimicrobial chemotherapy remains the cornerstone in the treatment of patients with severe, life threatening, bacterial infection. More...

Antimicrobial chemotherapy remains the cornerstone in the treatment of patients with severe, life threatening, bacterial infection. A delay in the administration of appropriate antibiotics is devastating.The rapid global expansion of antimicrobial resistance, particularly in Gram-negative bacteria, threatens to make antibiotic treatment ineffective (Rice, 2008). This PhD project explores the interaction between the important hospitalacquired pathogen Klebsiella pneumoniae and the emerging threat of carbapenem antibiotic resistance. Klebsiella pneumoniae commonly causes hospital-acquired infection that increasingly exhibits an antibiotic resistant phenotype (Pitout, et al., 2015). K. pneumoniae causes a range of invasive infections at multiple body sites. Klebsiella is frequently cultured in the respiratory tract and from the blood. The acquired plasmid mediated resistance to last line antibiotics, such as carbapenems, in this species has prompted significant concern that septic shock may become untreatable. Even in wards dealing with antibiotic sensitive K. pneumoniae, pulmonary sepsis in intensive care patients treated with appropriate antibiotics is more than 30% as they may be acuring antibiotic resistance from other bacteria during the infection (Koenig & Truwit, 2006). There is a significant predicted burden to K. pneumoniae in the carriage of very large plasmids (up to 250kb) conferring carbapenem resistance. Despite this, K. pneumoniae is the most common healthcare isolate in the United Kingdom exhibiting this phenotype (Trepanier, et al., 2017). The globally dominant enzymes KPC, OXA-48 and NDM1, which confer carbapenem resistance, are from distinct protein families. They are all capable of inactivating the carbapenem nucleus in the periplasmic space by hydrolysis. Their catalytic activity extends to all beta-lactams and most cephalosporin antibiotics. This leaves clinicians with inferior and often toxic antimicrobial alternatives. The project aim are: 1: To generate a murine model of carbapenem resistant pneumonia. 2: To generate the in vivo transcriptome of K. pneumoniae during pulmonary infection to identity conserved 1 This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ Less...