多重耐药性链球菌的进化路径研究获得成功

Despite penicillin¹（盘尼西林） and the dozens of antibiotics² that followed it, streptococcus（链球菌） bacteria have remained a major threat to health throughout the world. The reason: the superb（极好的，华丽的） evolutionary³ skills of this pathogen to rapidly alter its genetic⁴ makeup⁵. In a landmark⁶ paper published this week in Science, scientists from Rockefeller University and the Sanger Institute have used full genome sequencing to identify the precise steps in the molecular⁷ evolution of Streptococcus pneumoniae. Their research shows the changes the genome of this bacterium⁸ has undergone in time and during its massive geographic⁹ spread over the globe. According to the World Health Organization, fatal pneumococcal disease — mostly among children from underdeveloped countries — claims an estimated 4 million casualties per year. Humans are not only the primary targets of pneumococcal disease but also represent the major and possibly the only ecological¹⁰ reservoir on our planet for this bacterial¹¹ species, which colonizes¹² the nasopharynx（鼻咽） of preschool age children.

The researchers, led by the Sanger Institute's Stephen D. Bentley, used high resolution genome sequencing on clinical isolates¹³ of S. pneumoniae provided by a number of collaborating¹⁴ laboratories, including the Laboratory of Microbiology and Infectious Diseases at Rockefeller University, headed by Alexander Tomasz. With data available for the date, geographic site and infection site of these isolates, Bentley and colleagues were able to produce a roadmap for the evolution of a major multidrug resistant¹⁵ clones of pneumococci known as the PMEN clone 1, sequence type 81.

The scientists pinpointed¹⁶ the probable date of birth, 1970, and the likely birthplace, Europe, of this extremely successful multidrug resistant clone. The clone then spread to South and North America, South Africa and Asia. The presence of this clone in 12 New York City hospitals was demonstrated by Tomasz's group in 2001. Perhaps more importantly, the findings provide evidence that the mechanism¹⁷ of genetic change in S. pneumoniae is primarily not through acquisition（获得） of point mutations but more often — 88 percent of the time — through genetic recombination.

"The phenomenon of genetic transformation¹⁸, which led Oswald Avery and his Rockefeller colleagues in 1944 to identify DNA¹⁹ as the genetic material, is the very process that Streptococcus pneumoniae uses during evolution in its real in vivo environment," says Tomasz.

Other phenomena²⁰ first identified in the laboratory also appear in stages of pneumococcal evolution in vivo. For instance, at least some of the recombination changes observed among the clinical isolates seem to use the "competence²¹" system, a DNA uptake mechanism induced by a specific bacterial quorum²²（法定人数） sensing agent first detected by Tomasz and colleagues in laboratory experiments. Also, the mechanism of penicillin resistance, first identified by Tomasz and colleagues in the 1980s as changes in the affinity²³ of penicillin target proteins known as penicillin binding²⁴ proteins, or PBPs, is shown to involve the borrowing of genes²⁵ from other bacteria, a finding previously²⁶ documented in studies of individual penicillin resistant isolates.

"Perhaps the most fascinating part of the research is the description of how rapidly this clone has responded to massive in vivo（体内） interventions²⁷ in the clinical environment, such as the introduction of penicillin and other antibiotics and — more recently — the introduction of conjugate²⁸（结合的） anti-pneumococcal vaccines²⁹," says Tomasz. "These vaccines are directed against the most abundant serotypes of this bacterium, which are carried in the nasopharynx of children and which cause invasive disease."

"This research also demonstrates the importance of close collaborations between groups like the Sanger Laboratory, with expertise³¹ in high resolution genomic analysis, and laboratories that can provide carefully characterized collections of bacterial isolates, such as ours. This type of collaboration³⁰ fits well with the Rockefeller University's tradition of engaging in studies that combine clinical with translational science," says Tomasz. "Such an alliance between molecular biology and epidemiology（流行病学） promises further interesting insights into the mechanism of bacterial evolution in vivo. It may ultimately allow us to understand PMEN-1's secret of success – to learn why this clone was able to spread so widely while others died off."