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This paper is based on a presentation given at theLeverhulme Climate Symposium 2008: “Earth’s Climate:Past, Present and Future.” We thank the CoupledClimate-Carbon Cycle Model Intercomparison Project(C4MIP) for providing model outputs for this analysis.The contribution of C.J. was supported by the Defra andMoD Integrated Climate Programme (Contract number:GA01101, CBC/2B/0417_Annex C5).Supporting Online Materialwww.sciencemag.org/cgi/content/full/321/5896/1642/DC1MethodsFigs. S1 to S4References10.1126/science.1158907The need for new antibiotics is undis-puted (1). Recent studies estimate thatmore people die from the methi-cillin–resistant Staphylococcus aureus (MRSA)bacterium than from HIV in the United States(2), and the Centers for Disease Control andPrevention estimates that more than 90,000people die from hospital-acquired bacterialinfections in the United States each year.Numerous reports have illustrated the “perfectstorm” of rising bacterial resistance to antibi-otics and an industry pipeline ill-equipped toaddress the need for new antibacterial drugs(3, 4) (see the figure). Consequently, the reportsby Haydon et al. on page 1673 in this issue (5)and by Rasko et al. (6) are important becausethey validate and illustrate the therapeuticpotential of two new antibacterial drug targets.In addition, the paper by Hiratsuka et al. onpage 1670 in this issue (7) identifies a biosyn-thetic pathway that may provide new antibac-terial strategies for certain species of bacteria.Haydon et al. report the discovery of a classof drugs that targets the bacterial protein FtsZ.FtsZ is related to the human cytoskeletal pro-tein β-tubulin and is essential in bacterial celldivision in most Gram-positive and Gram-negative pathogens, where it polymerizes toform a ring at the mid cell that enables septumformation. The authors show by crystallo-graphic analysis that their lead molecule(PC190723) binds to the region of FtsZ that isanalogous to the site that the anticancer drugTaxol binds to in β-tubulin (Taxol interfereswith microtubule dynamics and blocks celldivision). Moreover, they show that PC190723possesses in vitro potency against MRSA, andis effective in a mouse model of S. aureusinfection. Importantly, through mutational andbacterial physiology experiments, Haydon et al.show that the antibacterial effect of PC190723is via inhibition of FtsZ. The discovery of theseinhibitors of FtsZ illustrates the potential ofthis protein as a novel and exploitable anti-bacterial drug target. Whereas inhibition of FtsZ prevents bacter-ial growth, Rasko et al. describe an alternativedrug approach that cripples the bacteria’s abil-ity to maintain an infection. The authors discov-ered a compound (LED209) that inhibits thebacterial enzyme QseC. This target is a histi-dine kinase that autophosphorylates upon sens-ing either host signaling molecules (the hor-mones norepinephrine and epinephrine) orbacterial molecules (called autoinducers) asso-ciated with quorum-sensing (cell-to-cell com-munication among bacteria). This phosphoryl-ation event leads to the expression of key viru-lence genes, and Escherichia coli with a mutantform of QseC is unable to trigger expression ofthese virulence genes and shows decreasedgrowth in an animal infection model. QseChomologs are found in most clinically impor-tant Gram-negative pathogens.Rasko et al. elegantly demonstratethat LED209 inhibits QseC-depend-ent expression of virulence genestriggered by either the autoinducerAI-3 or by epinephrine. In animalmodels of infection, LED209 wasnot effective in protecting againstE. coli infection, but oral dosing ofLED209 3 hours before and afterinfection with Salmonella typh-imurium protected mice from infec-tion. In addition, fewer bacteria wererecovered from the spleens and liv-ers of animals treated with LED209compared with controls. Therefore,this work demonstrates the potentialof an “antivirulence” strategy for tackling bac-terial infections. None of the currently availableantibiotics employ such a mechanism of action.Hiratsuka et al. illustrate the power of bacte-rial genomics to identify potential new targetsfor anti-infective strategies. Most microorgan-isms use a biosynthesis pathway encoded bythe men genes to produce menaquinone, amolecule needed for bacterial anaerobic respi-ration. However, the authors deduced thatsome bacteria such as Streptomyces coelicolor,Helicobacter pylori, and Campylobacter jejunilack these genes, yet still synthesize mena-quinone. To identify this new route of synthe-sis, the authors compared the genomes ofmicroorganisms that use the known men path-way with bacteria that lack the men genes. Thiseventually led to four candidate genes, each ofwhich were previously annotated as encoding“hypothetical proteins.” Each of these geneswas disrupted, and the resulting mutants allrequired menaquinone for growth. The authorsthen used biochemical and analytical ap-proaches to identify the various intermediatemolecules at each step in the new menaquinoneNew approaches for discovering the next generation of antibiotics are needed to combat the rise in bacteria that are resistant to current drugs.Desperately Seeking New AntibioticsDavid J. PayneMICROBIOLOGYAntibacterial Disease Performance Unit, Infectious DiseasesCenter of Excellence, GlaxoSmithKline, Collegeville, PA19426, USA. E-mail: [email protected] CONCERNS Global pandemic of MRSA infectionGlobal spread of drug resistance among common respiratorypathogens, including Streptococcus pneumoniae andMycobacterium tuberculosisEpidemic increases in multidrug-resistant (and increasingly, truly pan-resistant) Gram-negative bacilli (e.g., Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae)Bad bugs need drugs. Three major areas of concern that neednew antibiotics [as