Macrolide Resistance in Streptococcus pneumoniae Público

Abstract

Streptococcus pneumoniae, the pneumococcus, is an obligate commensal of the human nasopharynx, but an important opportunistic pathogen. The explosive, widespread use of macrolides in the last thirty years has been a strong selective pressure contributing to the expansion of macrolide-resistant S. pneumoniae. Macrolide resistance in pneumococci is primarily due to ribosomal methylation by a methyltransferase encoded by erm(B) and an efflux system encoded by mef(E)/mel, an operon of the macrolide efflux genetic assembly (Mega) element. These determinants are present on an expanding group of mobile composite genetic elements. Through a prospective study of invasive pneumococcal disease (IPD) using established population-based surveillance, the incidence of IPD and macrolide-resistant IPD (MR-IPD) in Atlanta, Georgia from 2003-2013 was studied. The heptavalent pneumococcal conjugate vaccine (PCV-7) introduced in 2000 was previously found to decrease IPD and MR-IPD caused by PCV-7 vaccine serotypes through individual and herd protection. In this work, we demonstrated a continued decline of IPD and MR-IPD caused by PCV-7 serotypes and observed "serotype replacement" by serotypes 7F for IPD and 19A for MR-IPD. The increase in MR-IPD from 2003-2009 was largely due to the clonal expansion of the serotype 19A clonal complex 320 isolates that contained Tn2010, a new composite mobile element with both erm(B) and mef(E)/mel. We documented a rapid decline of these isolates following PCV-13 introduction. By creating isogenic mutants, we assessed the contributions of dual macrolide resistance determinants in Tn2010 for pneumococcal fitness and macrolide resistance. We found erm(B) confers high-level macrolide resistance in Tn2010-containing strains, but mef(E)/mel encoded efflux remains functional. We also identified and assessed high-level macrolide-resistant IPD isolates caused by insertions of Mega, Mega-2.IVa and Mega-2.IVc, associated with the pneumococcal pathogenicity island. Deletion of mef(E)/mel eliminated macrolide resistance in these isolates. Using in vitro competition experiments, we found that, in the presence of erythromycin, high-level macrolide-resistant S. pneumoniae (conferred by erm(B) or Mega-2.IVa) have a growth fitness advantage. These data indicate the ability of S. pneumoniae to generate high-level macrolide resistance by efflux or ribosomal methylation, that either high-level mechanism affords a selective advantage, and that the efflux pump may have additional biological functions.

Table of Contents

Chapter 1 : Introduction pg 1

Chapter 2: A population-based assessment of the impact of 7- and 13-valent pneumococcal conjugate vaccines on macrolide-resistant invasive pneumococcal disease: emergence and decline of Streptococcus pneumoniae serotype 19A (CC320) with dual macrolide resistance mechanisms pg 36

Chapter 3: Composite mobile genetic elements disseminating macrolide resistance in Streptococcus pneumoniae pg 81

Chapter 4 : High-level macrolide resistance in Streptococcus pneumoniae pg 123

Chapter 5 : Final Discussion pg 164

Appendix A: Subversion of host recognition and defense systems by Francisella spp. pg 187

Appendix B: Rapid killing of Acinetobacter baumannii by polymyxins is mediated by a hydroxyl radical death pathway pg 210

Appendix C: A CRISPR-Cas system enhances envelope integrity mediating antibiotic resistance and inflammasome evasion pg 219

Appendix D: Pleomorphic structures in human blood are red blood cell-derived microvesicles, not bacteria pg 226

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Microbiology & Molecular Genetics
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, General Biology, Microbiology
Palabra Clave	Streptococcus pneumoniae Mega pneumococcal conjugate vaccines erm(B) Tn2010 macrolide resistance mef(E)/mel
Committee Chair / Thesis Advisor	Stephens, David S, Emory University
Committee Members	Shafer, William M, Emory University Rather, Phil N, Emory University Klugman, Keith P, Emory University Moran Jr., Charles, Emory University Read, Timothy D, Emory University Vidal Graniel, Jorge, Emory University

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