Antibiotics: Challenges, Mechanisms, Opportunities

490 Pages·2016·25.69 MB·English

by  Christopher Walsh

ANTIBIOTICS CHALLENGES WALSH ANTIBIOTICS
WENCEWICZ
MECHANISMS
OPPORTUNITIES
A
A chemocentric view of the molecular structures of antibiotics,
their origins, actions, and major categories of resistance
C H A L L E N G E S
N
Antibiotics: Challenges, Mechanisms, Opportunities focuses on antibiotics as small organic molecules from
both natural and synthetic sources. Understanding the chemical scaffold and functional group structures of
M E C H A N I S M S
the major classes of clinically useful antibiotics is critical to understanding how antibiotics interact selectively
with bacterial targets. T
This textbook details how classes of antibiotics interact with five known robust bacterial targets: cell wall O P P O R T U N I T I E S
I
assembly and maintenance, membrane integrity, protein synthesis, DNA and RNA information transfer, and
the folate pathway to deoxythymidylate. It addresses the universe of bacterial resistance, from the concept B
of the resistome to the three major mechanisms of resistance: antibiotic destruction, antibiotic active efflux,
and alteration of antibiotic targets. Antibiotics also covers the biosynthetic machinery for the major classes of
I
natural product antibiotics.
O
Authors Christopher Walsh and Timothy Wencewicz provide compelling answers to these questions:
• What are antibiotics?
• Where do antibiotics come from?
T
• How do antibiotics work?
• Why do antibiotics stop working? I
• How should our limited inventory of effective antibiotics be addressed?  C
Antibiotics is a textbook for graduate courses in chemical biology, pharmacology, medicinal chemistry,
microbiology, and biochemistry. It is also a valuable reference for microbiologists, biological and natural product
chemists, pharmacologists, and research and development scientists. S
“ This book provides all the information needed to understand antibiotic genetics, biochemistry,
OMC
mechanism of action, and resistance. Most importantly, Walsh and Wencewicz are optimistic
of the prospects of the discovery of novel therapeutic agents obtained by the manipulation PEH
PCA
of strains and biosynthetic pathways. This beautifully written book deserves to be read and
OHL
implemented by everyone, especially the pessimists who believe that the antibiotic era has
RAL
ended. In Antibiotics: Challenges, Mechanisms, Opportunities Walsh and Wencewicz provide E
the definitive, ultimate compendium of everything antibiotic.” TUNN
-- Julian Davies, Professor of Microbiology and Immunology, NISG
Life Sciences Institute, University of British Columbia, Vancouver IME
T
ISS
E
S
Christopher Walsh is a Harvard Timothy Wencewicz is a
Medical School professor emeritus faculty member in the
who serves as a senior advisor to Department of Chemistry
the ChEM-H Center at Stanford at Washington University
University. He has authored hundreds in St. Louis. After receiving
of papers and books, including the his Ph.D. at the University
predecessor to this title, Antibiotics: of Notre Dame, he was
Actions, Origins, Resistance (2003). a postdoctoral fellow in
Dr. Walsh is a member of the U.S. National Academy Christopher Walsh’s laboratory at the Harvard
of Sciences, the U.S. National Academy of Medicine, Medical School. Dr. Wencewicz’s research
the American Academy of Arts and Sciences, and the centers on antibiotic drug discovery, natural
American Philosophical Society and a co-recipient of product biosynthesis, and targeted drug
the 2010 Welch Prize in Chemistry. delivery across bacterial membranes.
ISBN 9781555819309
90000 >
CHRISTOPHER WALSH | TIMOTHY WENCEWICZ

9 781555 819309

Coverillustration:Snapshotofthe70SE.coliribosome(PDBfor50Sis2WDL;PDBfor30SandtRNAsis2WDK)
boundtothreeclassesofantibiotics.ThefigureshowsRNA(gray)andprotein(yellow)componentsoftheribosome
withassociatedtRNAsshownasbluecartoonsandboundantibioticsshownasredspacefillingspheres.Theterpenoid
tiamulinQ23bindstothe23SrRNAatthepeptidyltransferasecenter(PDB1XBP).Thenonribosomalpeptide
viomycinbindsattheinterfaceofthe50Sand30SsubunitsatthetRNAAsite(PDB4V7L).Thethiazolylpeptide
thiostreptonbindsattheperiphery,interactingwithaspecificpairof23SrRNAhelicesandaproline-richregionof
theL11proteinsubunit(PDB3CF5).(ImagecreatedusingPyMOL.)
Copyright©2016AmericanSocietyforMicrobiology.Allrightsreserved.Nopartofthispublicationmaybe
reproducedortransmittedinwholeorinpartorreusedinanyformorbyanymeans,electronicormechanical,
includingphotocopyingandrecording,orbyanyinformationstorageandretrievalsystem,withoutpermissionin
writingfromthepublisher.
Disclaimer:Tothebestofthepublisher’sknowledge,thispublicationprovidesinformationconcerningthesubject
mattercoveredthatisaccurateasofthedateofpublication.Thepublisherisnotprovidinglegal,medical,orother
professionalservices.Anyreferencehereintoanyspecificcommercialproducts,procedures,orservicesbytradename,
trademark,manufacturer,orotherwisedoesnotconstituteorimplyendorsement,recommendation,orfavored
statusbytheAmericanSocietyforMicrobiology(ASM).Theviewsandopinionsoftheauthor(s)expressedinthis
publicationdonotnecessarilystateorreflectthoseofASM,andtheyshallnotbeusedtoadvertiseorendorseany
product.
LibraryofCongressCataloging-in-PublicationData
Names:Walsh,Christopher,author.|Wencewicz,TimothyA.,author.
Title:Antibiotics:challenges,mechanisms,opportunities/byChristopher
T.WalshandTimothyA.Wencewicz.
Description:Washington,DC:ASMPress,[2016]|?2016|Includes
bibliographicalreferencesandindex.
Identifiers:LCCN2015045498(print)|LCCN2015047879(ebook)|ISBN
9781555819309(hardcover)|ISBN9781555819316()
Subjects:LCSH:Antibiotics.|Drugresistanceinmicroorganisms.
Classification:LCCRM267.W3582016(print)|LCCRM267(ebook)|DDC
615.3/29–dc23
LCrecordavailableathttp://lccn.loc.gov/2015045498
AllRightsReserved
PrintedintheUnitedStatesofAmerica
10 9 8 7 6 5 4 3 2 1
AddresseditorialcorrespondencetoASMPress,1752NSt.,N.W.,
Washington,DC20036-2904,USA
SendorderstoASMPress,P.O.Box605,Herndon,VA20172,USA
Phone:[phone]
Fax:[phone]
E-mail:[email protected]
Online:http://www.asmscience.org
.
Dedicated by CTW to Diana, Allison, Thomas, and Sean
.
Dedicated by TAW to Rachel, Grace, and Lucy

Contents
Preface ix–x
Section I ChallengesforAntibiotics 1
1 Antibiotics:InitialConceptsandConsiderations 4
2 MajorClassesofAntibioticsandTheirModesofAction 16
Section II Mechanisms:AntibioticActionbyBacterialTargetClass 33
3 AssemblyofthePeptidoglycanLayerofBacterialCellWalls 36
4 AntibioticsThatBlockPeptidoglycanAssemblyandIntegrity 68
5 AntibioticsThatDisruptMembraneIntegrity 102
6 AntibioticsThatBlockProteinSynthesis 114
7 AntibioticsThatTargetDNAandRNAInformationTransfer 148
8 AntibioticsThatBlockBiosynthesisoftheDNABuilding
BlockDeoxythymidylate 164
SectionIII Mechanisms:BacterialResistancetoAntibiotics 177
9 BacterialAntibioticResistance:Overview 180
10 AntibioticResistance:ModificationorDestructionoftheAntibiotic 198
11 AntibioticResistanceviaMembraneEffluxPumps 220
12 ResistanceviaTargetModification 230
13 Tuberculosis:AFormidableChallengeforAntibioticTherapy 252
vii
viii | CONTENTS
SectionIV Mechanisms:AntibioticBiosynthesis 273
14 AntibioticBiosynthesis:Principles 276
15 BiosynthesisofPeptideAntibiotics 288
16 BiosynthesisofPolyketideAntibiotics 320
17 BiosynthesisofOligosaccharide,Isoprenoid,and
C-PAntibioticClasses 344
Section V Opportunities 363
18 UnderexploitedPathwaysandTargetsforAntibiotics 366
19 ProspectsforNewMoleculesandNewTargets 398
References 421
Index 455
Preface
Overthepastdecade,manylinesofevidencehavecometogethertoemphasizethecriticalneedfor
newantibioticstotreatbacterialpathogens.Theserealizationshavegalvanizedthescientificcom-
munity as well as the global citizenry more generally. Infectious disease groups, government-
appointed expert panels,highpolitical officials, and the popular press have noted the prospect of
life-threateningbacterialinfectionstriggeringglobalsocietalcrises.
Therehasbeenaparallelrealizationandsetofeffortsseekingnewantiviraltreatmentsaspoten-
tiallyglobalepidemicsarise.Historically,antiviraldrugsandantibacterialdrugshavebeendiscov-
eredanddevelopedessentiallyindependentlywithalmostnocrossovertargetsorbenefits.Viruses
tend to be targeted by small molecules that block nucleic acid replication and inhibit proteases
needed to cut viral polyproteins into functional subunits; these approaches have not readily been
reframedforusefulantibacterials.Thisbookthendealsonlywithantibacterialagents,antibiotics,
andnotantivirals;albeittheneedforacontemporaryintegratedsummaryispressing.
Theneedfornext-generationversionsofantibioticsisnotnew.Thiswasthemotivationinwriting
aprecursortothisbookin2003:Antibiotics:Actions,Origins,Resistance.Ithasbeentrueforevery
class of antibiotic introduced into wide human clinical use since the antibiotic era began in the
1930sthatresistantorganismsareselectedforandeventuallybecomeabundantinhumaninfections.
Others have noted, appropriately, the complexity of the cycles of development of antibiotics,
developmentofresistance,andneedfornewantibiotics.Theneedforconservationandprolongation
ofusefullifetimesoftheexistingantibioticsportfoliohasbothhealthandeconomicconsequences.
Marketincentivesoverthepast2decadeshavebeenviewedasinsufficientforlargepharmacom-
paniestoinvestinantibioticsresearch.Alternativestotraditionalsmall-moleculeantibioticsrange
from vaccines with a preventative role to biologics, whetherantibodies or lytic phage treatments,
buttheuseofthesetherapieshasnotyetbecomewidespread.
Amidthissetofcomplexities,oneconstantisthatnewantibioticsarealwaysneededtodealwith
wavesofresistantbacteriathatbecomeinuredtoanyantibioticclassthatiswidelydisseminatedfor
treatment.Givenourbeliefthatnewclassesofantibioticsareacutelyneededtofillthefrontendofthe
antibioticcycles,theapproachinthismonograph,Antibiotics:Challenges,Mechanisms,Opportunities,
ischemocentric.
Thechallengesaremanyandlayered,asnotedinpassingabove,butchiefamongthemishowto
findnewmolecules,whetherthroughthediscoveryofnovelvariantsfromnatureorthecreativityof
ix