o 



o 

 > 



plasmid, that has the necessary gene. Plas- 

 mids that confer resistance to many other 

 antibiotics are also now widespread. Some 

 plasmids even carry genes that enable 

 them to confer resistance to more than one 

 antibiotic. 



Other bacteria have followed a different 

 route to penicillin resistance: they have 

 changed their PBP enzymes so that peni- 

 cillin will no longer bind to them. This is 

 true of Neisseria, a genus that includes the 

 causative agents of gonorrhea and of some 

 cases of bacterial meningitis. 



The gene coding for the PBP2 enzyme 

 (the most important of the peniciUin bind- 

 ing proteins) was analyzed for several 

 penicillin-sensitive strains of Neisseria 

 meningitidis and for a number of resistant 

 strains. The sensitive strains were all very 

 similar to one another, and their differ- 

 ences had little effect on the sequence of 

 amino acids (protein building blocks) in 

 the PBP2 enzyme. The genes belonging to 

 the resistant strains, however, differed sig- 

 nificantly. Each gene was a mosaic, con- 

 sisting of DNA pieces that were very sim- 

 ilar to the corresponding pieces in the gene 

 from the sensitive strains, along with 

 pieces that differed in about 20 percent of 

 their bases (the chemical units in DNA 

 that determine what amino acids will be 

 inserted in the protein). 



The variant pieces must have been ac- 

 quired from another bacterium. We know 

 that Neisseria cells actively take up bits of 

 DNA from their surroundings, preferring 

 DNA similar to their own. The DNA is 

 broken into pieces, and some of the pieces 

 are slotted into the bacterial chromosome, 

 replacing those that are already there. This 

 process of "transformation" is analogous 

 to sex in higher organisms: it is a means 

 whereby genetic material from two ances- 

 tors is combined in a single descendant. 

 The difference is that in the sexual process, 

 the new individual gets half its DNA from 

 each parent, whereas in transformation, 

 the recipient cell gets only a small fraction 

 of its DNA from a donor But from an evo- 

 lutionary point of view, the two processes 

 have similar consequences: favorable mu- 

 tations occurring in different ancestors can 

 combine in a single descendant. 



In the case of Neisseria, we know 

 where the introduced blocks of DNA 

 come from. The genus includes not only 

 the bacteria causing meningitis and gonor- 

 rhea but also a number of harmless species 

 found in the human throat. Some of these 

 are naturally resistant to penicillin, and 

 were so before the clinical use of antibi- 

 otics began. The introduced blocks are al- 



Genetic transformation has enabled 

 strains o/Streptococcus pneumoniae, 

 which cause respiratory disease, to resist 

 many antibiotics. The bacteria (within the 

 globules) also combat the body's natural 

 immune defenses by enveloping 

 themselves in capsules of secreted 

 material. 



most identical to the PBP2 genes found in 

 one or the other of two harmless species, 

 N. flavescens and N. mucosa. Thus N. 

 meningitidis evolved resistance to peni- 

 cillin by acquiring DNA from related spe- 

 cies that were already resistant. The same 

 is true of M gonorrhoeae. 



The PBP genes in resistant Streptococ- 

 cus pneumoniae, an important cause of 

 respiratory disease, also show a mosaic 

 structure, and we are confident that they 

 too were acquired by genetic transforma- 

 tion. The donor species, however, has not 

 yet been found. (S. pneumoniae, inciden- 

 tally, was the bacterium in which bacterial 

 transformation was first discovered by F. 

 Griffith in 1928. Oswald Avery then 

 demonstrated that the transforming factor 

 was DNA, and this led James Watson and 

 Francis Crick to study the structure of 

 DNA. So began the molecular biology 

 revolution.) 



Does transformation play a comparable 

 role in other bacteria now developing re- 

 sistance to antibiotics? We cannot be sure. 

 Many bacteria, including the geneticist's 

 favorites, Escherichia and Salmonella, do 

 not actively obtain outside DNA — they 

 are not, to use the jargon of microbial ge- 

 netics, "competent for transformation." 

 But even these bacteria can acquire DNA 

 from other cells. For example, bacterio- 

 phages (viruses that Uve in bacteria) some- 

 times carry bacterial DNA into a new host 

 cell by accident. 



These and other forms of bacterial evo- 

 lution, with the consequent spread of an- 

 tibiotic resistance, are undermining our 

 ability to treat infectious diseases, includ- 

 ing the infections that can wreak havoc 

 with any form of surgery. Further cause 

 for concern is the increasing use of bacte- 

 ria in industrial processes. If genetically 

 engineered organisms are released into the 

 environment, the genes in those organisms 

 are unlikely to remain where we put them. 

 We therefore have to ask not only whether 

 the released organism is harmless but also 

 whether the genes it contains are harmless. 



40 Natural History 6/94 



