Recently, we have obtained direct evidence of massive and repeated HGT among pneumococcal strains during a polyclonal pediatric chronic infection that supports the above hypotheses. In this study, we identified a dominant strain

that, over a period of 7 months, underwent more than a dozen transformation events, leading to the replacement of approximately 7% of its genome. The fact that we were able to recover multiple recombinant strains when isolating only one strain per time point suggests that these recombinant strains did indeed have a selective advantage in the host environment. Our laboratory, as well as those of our colleagues (Tettelin et al., 2005; Hall et al., 2010; Harris et al., 2010) have used whole-genome sequencing to characterize the sizes of the supragenomes and determine the average Talazoparib molecular weight number of gene possession differences of multiple independent clinical or environmental strains for over two dozen bacterial species including Escherichia coli, H. influenzae, Pseudomonas fluorescens, S. pneumoniae, Streptococcus agalactiae, S. aureus, and G. vaginalis. These studies have validated RGFP966 manufacturer the DGH for all species examined and demonstrated that the noncore genes in each strain comprise on average one-fifth to one-third of each strain’s genome and that the species-level supragenomes are often three

to four times the size of the core genomes (Tettelin et al., 2005; Hiller et al., 2007; Hogg et al., 2007; Hall et al., 2009; Ahmed et al., submitted; Donati et al., submitted). The predictions of the DGH and the observation that there are enormous gene possession differences among the strains of nearly all bacterial species combine to suggest that during chronic infections, the bacteria, through HGT mechanisms, Thymidylate synthase create a ‘cloud’ of related strains, each with distinct antigenic and virulence

profiles that serve to keep the bacterial population ‘one step ahead of the host’s immune system’. Such a strategy would be analogous to what has been demonstrated for other classes of chronic pathogens such as HIV (Lee et al., 2009) and the trypanosomes that use error-prone nucleic acid polymerases and programmed gene cassette swapping to generate a cloud of diverse strains to avoid immune clearance. Thus, it would appear that diversity generation, regardless of its precise mechanism, is key to the maintenance of a chronic infectious disease state. These observations on diversity generation by bacteria during chronic infectious processes suggest that interventional therapeutic strategies could be developed to target this aspect of microbial pathogenesis. One such strategy would be STAMP (specific targeted antimicrobial peptides) technology, wherein a bifunctional peptide is constructed that contains a generic bacteriolytic segment and a species-specific ligand for targeting. By targeting the DNA uptake system of S. mutans, the Shi laboratory has demonstrated a multilog kill of S.