Multidrug treatments are increasingly important in medicine and for probing biological systems. Although many studies have focused on interactions between specific drugs, little is known about the system properties of a full drug interaction network. Like their genetic counterparts, two drugs may have no interaction, or they may interact synergistically or antagonistically to increase or suppress their individual effects. Here we use a sensitive bioluminescence technique to provide quantitative measurements of pairwise interactions among 21 antibiotics that affect growth rate in Escherichia coli. We find that the drug interaction network possesses a special property: it can be separated into classes of drugs such that any two classes interact either purely synergistically or purely antagonistically. These classes correspond directly to the cellular functions affected by the drugs. This network approach provides a new conceptual framework for understanding the functional mechanisms of drugs and their cellular targets and can be applied in systems intractable to mutant screening, biochemistry or microscopy.

Prokaryotic genomes are substantially diverse, even when from closely related species, with the resulting phenotypic diversity representing a repertoire of adaptations to specific constraints. Within the microbial population, genome content may not be fixed, as changing selective forces favor particular phenotypes; however, organisms well adapted to particular niches may have evolved mechanisms to facilitate such plasticity. The highly diverse Helicobacter pylori is a model for studying genome plasticity in the colonization of individual hosts. For H. pylori, neither point mutation, nor intergenic recombination requiring the presence of multiple colonizing strains, is sufficient to fully explain the observed diversity. Here we demonstrate that H. pylori has extensive, nonrandomly distributed repetitive chromosomal sequences, and that recombination between identical repeats contributes to the variation within individual hosts. That H. pylori is representative of prokaryotes, especially those with smaller (<2 megabases) genomes, that have similarly extensive direct repeats, suggests that recombination between such direct DNA repeats is a widely conserved mechanism to promote genome diversification. P rokaryotes that successfully colonize niches for extended periods of time must be capable of adapting to changing environmental stresses (1). Genomic diversity, caused by spontaneous point mutation, intragenomic rearrangement, and horizontal gene acquisition (2), creates a phenotypically diverse population from which the most-fit variants are selected. Colonization of the primate stomach by Helicobacter pylori is prolonged, usually persisting for decades without host clearance (3). That essentially all H. pylori isolates obtained from unrelated individuals are genetically distinguishable (4), and that diverse subclones have been identified in individual hosts (5-7) suggest that persistence may be facilitated by the organism's ability to adapt to dynamic environments by continuous change (8). HIV and other pathogenic viruses that persistently infect hosts employ similar strategies of ''quasispecies'' development to increase fitness success (9).For H. pylori, neither spontaneous point mutation (10) nor recombination with other bacterial cells (11) is sufficient to explain observed intrahost genetic variation (5, 7). Computational analysis of the fully sequenced H. pylori strain 26695 (12) indicates numerous direct DNA repeats (13, 14); however, these studies do not demonstrate a role for repeats through experimental analyses, provide evidence that these repeat structures are involved in any biologic function, or assess how the nonrandom distribution of repeats may affect the physiology or evolution of the host organism. Because recombination involving direct repeats allows for deletion or duplication of intervening sequences (15), we sought to determine the extent to which H. pylori uses repetitive DNA sequences to generate diversity. Our observations provide evidence that the presence of extensive, nonrandomly distribu...

Recombination is a fundamental mechanism for the generation of genetic variation. Helicobacter pylori strains have different frequencies of intragenomic recombination, arising from deletions and duplications between DNA repeat sequences, as well as intergenomic recombination, facilitated by their natural competence. We identified a gene, hp1523, that influences recombination frequencies in this highly diverse bacterium and demonstrate its importance in maintaining genomic integrity by limiting recombination events. HP1523 shows homology to RecG, an ATP-dependent helicase that in Escherichia coli allows repair of damaged replication forks to proceed without recourse to potentially mutagenic recombination. Cross-species studies done show that hp1523 can complement E. coli recG mutants in trans to the same extent as E. coli recG can, indicating that hp1523 has recG function. The E. coli recG gene only partially complements the hp1523 mutation in H. pylori. Unlike other recG homologs, hp1523 is not involved in DNA repair in H. pylori, although it has the ability to repair DNA when expressed in E. coli. Therefore, host context appears critical in defining the function of recG. The fact that in E. coli recG phenotypes are not constant in other species indicates the diverse roles for conserved recombination genes in prokaryotic evolution.

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