Microbiology: Antibiotic stops ‘ping-pong’ match
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NATURE|Vol 441| 18 May 2006 NEWS & VIEWS 293 Doppler wobble. Second, the reduced stellar brightness shifts the habitable zone inwards, reducing the orbital period of a habitable planet and further increasing the Doppler wobble. Should astronomers succeed in trans- ferring the precision achieved by Lovis et al. 2 to low-mass stars, they might just turn up a few planets akin to our own. What the Doppler method will, unfortu- nately, never reveal is the composition of the planets it detects. An exciting synergy there- fore surely exists between such high-precision Doppler measurements and measurements to be made by two planned satellite missions, the COROT mission 4 led by the French space agency CNES, and NASA’s Kepler mission 5 . Both spacecraft will seek to identify rocky planets by the complementary method of tran- sits 6 , in which a planet is revealed as it crosses the face of its parent star by a minute dimming of that star’s light. By observing both Doppler signals and transits, both the mass and physical size of a planet can be estimated. That in turn yields a density and (by inference) a composi- tion. Previous limits on the Doppler method implied that any terrestrial planets detected by COROT and Kepler would not receive corrob- orative Doppler measurements. Excitingly, Lovis and colleagues 2 have given us cause to rethink this pessimistic assumption. ■ David Charbonneau is in the Department of Astronomy, Harvard University, 60 Garden Street, Cambridge, Massachusetts 02138, USA. e-mail: [email protected] 1. Udry, S., Fischer, D. A. & Queloz, D. in Protostars and Planets V (eds Reipurth, B., Jewitt, D. & Keil, K.) (Univ. Arizona Press, Tucson, in the press). 2. Lovis, C. et al. Nature 441, 305–309 (2006). 3. Beichman, C. A. et al. Astrophys. J. 626, 1061–1069 (2005). 4. Bordé, P., Rouan, D. & Léger, A. Astron. Astrophys. 405, 1137–1144 (2003). 5. Basri, G., Borucki, W. J. & Koch, D. New Astron. Rev. 49, 478–485 (2005). 6. Charbonneau, D., Brown, T. M., Burrows, A. & Laughlin, G. in Protostars and Planets V (eds Reipurth, B., Jewitt, D. & Keil, K.) (Univ. Arizona Press, Tucson, in the press). HD 69830 is no stranger to the spotlight. Last year, researchers using the NASA Spitzer Space Telescope announced that it probably possesses an asteroid belt 3 — the only star sim- ilar in mass and age to the Sun that is known to have one. This conclusion came from the observation that the star was brighter than expected at infrared wavelengths, suggesting the presence of grains of dust that were small and were located within 1 AU of the star. At that distance, small grains could not survive very long, as the star’s light would cause them either to fall inwards towards the star, or be blown outwards. The researchers therefore inferred that the grains must be constantly replenished by material spun off in collisions of large bod- ies in an asteroid belt. Notably, the implied mass of HD 69830’s asteroid belt is roughly 25 times that of our own, seemingly in line with the beefed-up values of the planetary masses. Intriguingly, these researchers also posited 3 the existence of an unseen planet that quietly shepherded the asteroid belt in its orbit. It would seem that Lovis et al. have found the (plural) shepherds. Working with the converse logic, they consider 2 the gravitational influ- ence of their three planets on an asteroid belt, and find that its position must be constrained to be either close to the star (0.3–0.5 AU) or far from it (beyond 0.8 AU). The earlier infrared observations favour the former location, which places the belt between the orbits of the centre and the outermost planet, but whether this location is truly stable and consistent with the infrared observations remains an open question. In the Solar System, the asteroid belt lies near 2.6 AU, between the orbits of Mars and Jupiter. The difference in its location in the HD 69830 system is surely a clue to differences in that star’s planet-formation history. One of the great quests of astronomy is to discover a small, rocky, Earth-like planet orbiting within the ‘habitable zone’ — the range of distances from a star for which the ambient temperature would permit a planet with liquid water and, perhaps, life as we know it. For the Sun, which is comparatively large and hot for our Galaxy, this orbital distance is great enough that the Doppler wobble induced by Earth would be a measly 9 cm s ǁ1 , nearly an order of magnitude below even the exquisite measurement precision established by Lovis and colleagues. But most neighbour- ing stars are significantly less massive and cooler than the Sun, so a search for habitable planets using the Doppler method is feasible for two reasons. First, the lower stellar mass means an Earth-mass planet will cause a larger Figure 1 | Three’s company. How the planetary system of the Sun-like star HD 69830 might look, according to Lovis and colleagues 2 . Three Neptune-mass planets orbit the star on near-circular orbits at around 0.08 AU, 0.19 AU and 0.63 AU (where 1 AU is the distance from Earth to the Sun). Considerations of the gravitational influence of the three planets puts the most likely position for an asteroid belt, the existence of which has been inferred by measurements of infrared radiation 3 , at between 0.3 and 0.5 AU. MICROBIOLOGY Antibiotic stops ‘ping-pong’ match Eric D. Brown As bacteria become resistant to existing drugs, there is a need for antibiotics with new modes of action. Such a compound has been found, and it works by binding to an intermediate in the catalytic cycle of its target. Pathogenic bacteria have developed strains that are resistant to almost all antibiotics in use today. Particularly worrisome are infections by a large group of bacteria classified as being Gram-positive, such as staphylococci and ente- rococci, which cause pneumonia and other, often fatal, infections. The problem is high- lighted by the emergence of multiply-drug- resistant strains of these organisms — so-called superbugs — that are resistant to vancomycin 1 , a drug widely recognized as the last line of defence in many Gram-positive bacterial infec- tions. On page 358 of this issue 2 , Wang and col- leagues report the discovery of a new antibiotic, platensimycin, that has potent antibacterial activity against these Gram-positive pathogens. Nature Publishing Group ©2006
Transcript of Microbiology: Antibiotic stops ‘ping-pong’ match
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Doppler wobble. Second, the reduced stellarbrightness shifts the habitable zone inwards,reducing the orbital period of a habitableplanet and further increasing the Dopplerwobble. Should astronomers succeed in trans-ferring the precision achieved by Lovis et al.2
to low-mass stars, they might just turn up afew planets akin to our own.
What the Doppler method will, unfortu-nately, never reveal is the composition of theplanets it detects. An exciting synergy there-fore surely exists between such high-precisionDoppler measurements and measurements tobe made by two planned satellite missions, the COROT mission4 led by the French spaceagency CNES, and NASA’s Kepler mission5.Both spacecraft will seek to identify rockyplanets by the complementary method of tran-sits6, in which a planet is revealed as it crossesthe face of its parent star by a minute dimmingof that star’s light. By observing both Dopplersignals and transits, both the mass and physicalsize of a planet can be estimated. That in turnyields a density and (by inference) a composi-tion. Previous limits on the Doppler methodimplied that any terrestrial planets detected byCOROT and Kepler would not receive corrob-orative Doppler measurements. Excitingly,Lovis and colleagues2 have given us cause torethink this pessimistic assumption. ■
David Charbonneau is in the Department ofAstronomy, Harvard University, 60 GardenStreet, Cambridge, Massachusetts 02138, USA.e-mail: [email protected]
1. Udry, S., Fischer, D. A. & Queloz, D. in Protostars and PlanetsV (eds Reipurth, B., Jewitt, D. & Keil, K.) (Univ. ArizonaPress, Tucson, in the press).
2. Lovis, C. et al. Nature 441, 305–309 (2006).3. Beichman, C. A. et al. Astrophys. J. 626, 1061–1069
(2005).4. Bordé, P., Rouan, D. & Léger, A. Astron. Astrophys. 405,
1137–1144 (2003).5. Basri, G., Borucki, W. J. & Koch, D. New Astron. Rev. 49,
478–485 (2005).6. Charbonneau, D., Brown, T. M., Burrows, A. & Laughlin, G.
in Protostars and Planets V (eds Reipurth, B., Jewitt, D. &Keil, K.) (Univ. Arizona Press, Tucson, in the press).
HD 69830 is no stranger to the spotlight.Last year, researchers using the NASA SpitzerSpace Telescope announced that it probablypossesses an asteroid belt3 — the only star sim-ilar in mass and age to the Sun that is known tohave one. This conclusion came from theobservation that the star was brighter thanexpected at infrared wavelengths, suggestingthe presence of grains of dust that were smalland were located within 1 AU of the star. At thatdistance, small grains could not survive verylong, as the star’s light would cause them eitherto fall inwards towards the star, or be blownoutwards. The researchers therefore inferredthat the grains must be constantly replenishedby material spun off in collisions of large bod-ies in an asteroid belt. Notably, the impliedmass of HD 69830’s asteroid belt is roughly 25times that of our own, seemingly in line withthe beefed-up values of the planetary masses.
Intriguingly, these researchers also posited3
the existence of an unseen planet that quietlyshepherded the asteroid belt in its orbit. Itwould seem that Lovis et al. have found the(plural) shepherds. Working with the converselogic, they consider2 the gravitational influ-ence of their three planets on an asteroid belt,and find that its position must be constrainedto be either close to the star (0.3–0.5 AU) or farfrom it (beyond 0.8 AU). The earlier infraredobservations favour the former location,which places the belt between the orbits of thecentre and the outermost planet, but whetherthis location is truly stable and consistent withthe infrared observations remains an openquestion. In the Solar System, the asteroid beltlies near 2.6 AU, between the orbits of Marsand Jupiter. The difference in its location in theHD 69830 system is surely a clue to differencesin that star’s planet-formation history.
One of the great quests of astronomy is todiscover a small, rocky, Earth-like planetorbiting within the ‘habitable zone’ — therange of distances from a star for which theambient temperature would permit a planetwith liquid water and, perhaps, life as we knowit. For the Sun, which is comparatively largeand hot for our Galaxy, this orbital distance is great enough that the Doppler wobbleinduced by Earth would be a measly 9 cm s�1,nearly an order of magnitude below even theexquisite measurement precision establishedby Lovis and colleagues. But most neighbour-ing stars are significantly less massive andcooler than the Sun, so a search for habitableplanets using the Doppler method is feasiblefor two reasons. First, the lower stellar massmeans an Earth-mass planet will cause a larger
Figure 1 | Three’s company. How the planetary system of the Sun-like star HD 69830 might look,according to Lovis and colleagues2. Three Neptune-mass planets orbit the star on near-circular orbits ataround 0.08 AU, 0.19 AU and 0.63 AU (where 1 AU is the distance from Earth to the Sun). Considerationsof the gravitational influence of the three planets puts the most likely position for an asteroid belt, theexistence of which has been inferred by measurements of infrared radiation3, at between 0.3 and 0.5 AU.
MICROBIOLOGY
Antibiotic stops ‘ping-pong’ matchEric D. Brown
As bacteria become resistant to existing drugs, there is a need forantibiotics with new modes of action. Such a compound has been found,and it works by binding to an intermediate in the catalytic cycle of its target.
Pathogenic bacteria have developed strainsthat are resistant to almost all antibiotics in usetoday. Particularly worrisome are infections bya large group of bacteria classified as beingGram-positive, such as staphylococci and ente-rococci, which cause pneumonia and other,often fatal, infections. The problem is high-lighted by the emergence of multiply-drug-
resistant strains of these organisms — so-calledsuperbugs — that are resistant to vancomycin1,a drug widely recognized as the last line ofdefence in many Gram-positive bacterial infec-tions. On page 358 of this issue2, Wang and col-leagues report the discovery of a new antibiotic,platensimycin, that has potent antibacterialactivity against these Gram-positive pathogens.
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In the past 40 years, only two antibioticsrepresenting new chemical classes havereached the clinic, namely linezolid (an oxazo-lidinone3) and daptomycin (a lipopeptide4).Most classes of antibiotic were discovered inthe 1940s and 1950s, and are directed at a fewspecific aspects of bacterial physiology —mainly biosynthesis of the cell wall, and ofDNA and proteins. Subsequent tweaking ofthese chemical scaffolds has produced most of today’s antibiotics. It is believed that wide-spread drug resistance among bacterialpathogens is due to the limited choice ofantibiotics that exploit a relatively narrowrange of mechanisms. Wang and colleagues’report2 of a compound representing a novelclass of antibiotic with activity against Gram-positive bacterial pathogens is thus particu-larly exciting, with the added bonus thatplatensimycin is effective against multiply-drug-resistant strains of staphylococci andenterococci.
The report reads like a textbook of modernantibacterial drug discovery, beginning with ascreen of 250,000 extracts from drug-produc-ing microorganisms. What follows is a seriesof elegant studies, spanning bacterial genetics,biochemistry, pharmacology and structuralbiology, and leading to the discovery of a smallmolecule derived from Streptomyces platensisthat targets a seldom-exploited weakness inbacteria: fatty-acid biosynthesis. Fatty acids —organic acids with long hydrocarbon chains of between 8 and 18 carbon atoms — are the building-blocks of cell membranes and
bacterial surfaces. They are produced throughthe repetitive action of biosynthetic machinerythat elongates the chains two carbon atoms at a time. The target of platensimycin is a key enzyme component of this machinery: �-ketoacyl-ACP (acyl carrier protein) syn-thase, also known as FabF.
The FabF enzyme mediates a reaction thathas a fascinating catalytic cycle (Fig. 1). Thefatty acid to be elongated is first transferredfrom ACP to FabF, leaving the fatty acid boundto the enzyme through an active-site aminoacid (cysteine), affording a transient acyl–enzyme intermediate5. The source of extendercarbon atoms is a molecular fragment knownas a malonyl group, which is attached to ACP.The malonyl–ACP substrate is bound by FabF,and then loses carbon dioxide to produce areactive two-carbon unit. The reactive unitattacks the acyl–enzyme intermediate andyields an elongated product that is releasedfrom the enzyme. Enzymologists describe thisseries of reactions as ‘ping-pong’. This looseanalogy refers to the way that the first sub-strate ‘pings’ into the active site and the firstproduct ‘pongs’ out, leaving the enzymealtered, so that the second substrate does thesame as the first, leading to a product knownas �-ketoacyl-ACP (Fig 1). There is thus astrict order involving the addition of fattyacid–ACP and then malonyl–ACP.
Wang et al.2 provide an account of some terrific detective work that revealed that platen-simycin binds only to the acyl–enzyme inter-mediate. Such intermediates are short-lived,
Figure 1 | The catalytic cycle of FabF for fatty-acid biosynthesis in bacteria. a, The fatty-acid fragment (in blue; R represents a general hydrocarbon chain) is transferred from a sulphur atom on acyl carrier protein (ACP) to a sulphur atom on cysteine in the FabF active site. In response, the active site becomes more open. b, Malonyl–ACP substrate (in green) binds to the acyl–enzymeintermediate, and loses carbon dioxide. The fatty-acid fragment is transferred from the active site, adding to the remains of the malonyl–ACP substrate, and thus extending the chain. c, Wang et al.2 show that platensimycin inhibits the cycle by binding to the acyl–enzyme intermediate,preventing the addition of malonyl–ACP substrate — blocking fatty-acid biosynthesis, and so acting as an antibiotic.
CO2+
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typically with lifetimes of the order of milli-seconds, and so are difficult to observe. Toovercome this problem, the researchers cre-ated a mimic of the acyl–enzyme intermediate.They prepared a variant of the FabF enzyme in which the cysteine of the active site wasreplaced with the amino acid glutamine. The chemical group that forms the side chain of glutamine mimics a bound fatty acid.The variant enzyme bound platensimycin with high affinity, and a high-resolution crystal structure of the complex of variantFabF with the new antibiotic was obtained.The structure reveals that formation of the acyl–enzyme intermediate is accompanied by structural changes that open up the activesite, permitting binding of platensimycin in such a way that it blocks the addition of malonyl–ACP.
Platensimycin is a significant new antibac-terial compound with an extraordinary mech-anism, but it is not the first antibiotic known toinhibit bacterial fatty-acid biosynthesis6,7. Iso-niazid and triclosan are synthetic compoundsthat also target this pathway. Isoniazid has aclinical niche in treating tuberculosis in combination with other antibiotics, whereastriclosan has been widely used in soaps andplastics. In addition, cerulenin and thiolacto-mycin are natural products derived from fungithat target the same specific biosynthetic reac-tion as platensimycin in bacteria. That neitherof these fungus-derived compounds has founda use in the clinic is testimony to the high stan-dards required for a successful new antibiotic.Pharmaceutical companies have generallyretreated from the field of antibacterial drugs,concentrating instead on chronic diseases withperceived product development and marketadvantages8. It is heartening, therefore, thatplatensimycin has been discovered and char-acterized by workers at Merck.
Wang et al. show that this antibiotic is effec-tive in a mouse model of infection. The pathahead remains a long one that includes furtherpreclinical study, and, if these studies are suc-cessful, extensive clinical trials for safety andefficacy in humans. Platensimycin is never-theless the most potent inhibitor reported so far for FabF, and thus its discovery is anencouraging one. ■
Eric D. Brown is in the Department ofBiochemistry and Biomedical Sciences,McMaster University, Hamilton, Ontario L8N 3Z5, Canada.e-mail: [email protected]
1. Weigel, L. M. et al. Science 302, 1569–1571 (2003).2. Wang, J. et al. Nature 441, 358–361 (2006).3. Ford, C. W., Zurenko, G. E. & Barbachyn, M. R. Curr. Drug
Targets Infect. Disord. 1, 181–199 (2001).4. LaPlante, K. L. & Rybak, M. J. Expert Opin. Pharmacother. 5,
2321–2331 (2004).5. Price, A. C., Rock, C. O. & White, S. W. J. Bacteriol. 185,
4136–4143 (2003).6. Campbell, J. W. & Cronan, J. E. Jr Annu. Rev. Microbiol. 55,
305–332 (2001).7. Heath, R. J., White, S. W. & Rock, C. O. Appl. Microbiol.
Biotechnol. 58, 695–703 (2002).8. Projan, S. J. Curr. Opin. Microbiol. 6, 427–430 (2003).
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