| Summary: | <p><em>Streptococcus pneumoniae</em> (the pneumococcus) is a bacterial pathogen responsible for >1.6 million annual deaths globally. Pneumococcal penicillin-resistance is conferred by acquisition of ‘altered’ penicillin-binding protein (pbp) genes. The first penicillin-nonsusceptible pneumococci were identified in the late 1960s. Global pneumococcal penicillin-nonsusceptibility rates rapidly increased in the 1980s/90s.</p><p>Since 2000, protein-conjugate vaccines, targeting 7, 10 or 13 of the ≥94 different pneumococcal capsule types (serotypes), have been introduced in many countries. Following vaccine implementation there has been a decline in vaccine-type pneumococcal disease and an increase in non-vaccine-type disease. These epidemiological changes result from “serotype replacement” and/or “serotype switching”. The former describes the expansion of non-vaccine-type clones in the absence of vaccine-type pneumococci. The latter describes serotype change following recombination at the capsule polysaccharide synthesis (cps) locus.</p><p>To fully understand how pneumococci respond to vaccine- and antibiotic-induced selective pressures, we must better understand the evolutionary history of this pathogen. This thesis describes the study of a global collection of 426 pneumococci, dated 1937 - 2007. Serotype, genotype and penicillin-susceptibility data were collected. Nucleotide sequences of three pbp genes (for 389 isolates) and whole-genome sequences (for 96 isolates) were also generated.</p><p> The data demonstrated the long-term persistence of certain clones within pneumococcal populations, and that pbp and large-fragment (>30 kb) cps ± pbp recombination was occurring prior to both widespread antibiotic use and vaccine implementation. The data highlighted the promiscuous nature of the globally-distributed PMEN1 clone and its contribution to the spread of pneumococcal penicillin-resistance. PMEN1 also donated multiple, large regions (1.7 - 32.3 kb) of its genome to at least two un-related clones. Finally, six “Tn916-like” genetic elements, conferring resistance to non-penicillin antibiotics, were newly identified. These included two of the oldest ever described.</p><p>These results provided a unique insight into the history of pneumococcal evolution and the importance of genetic recombination.</p>
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