Challenges of Antibacterial Discovery Lynn L

CLINICAL MICROBIOLOGY REVIEWS, Jan. 2011, p. 71–109 Vol. 24, No. 1 0893-8512/11/$12.00 doi:10.1128/CMR.00030-10 Copyright © 2011, American Society for Microbiology. All Rights Reserved. Challenges of Antibacterial Discovery Lynn L. Silver* LL Silver Consulting, LLC, 955 S. Springfield Ave., Unit C403, Springfield, New Jersey 07081 INTRODUCTION .........................................................................................................................................................72 The Discovery Void...................................................................................................................................................72 Class Modifications versus Novel Classes.............................................................................................................72 BACKGROUND............................................................................................................................................................72 Early Screening—a Brief and Biased Philosophical History .............................................................................72 The Rate-Limiting Steps of Antibacterial Discovery ...........................................................................................74 The Multitarget Hypothesis ....................................................................................................................................74 ANTIBACTERIAL RESISTANCE ..............................................................................................................................75 Endogenous versus Exogenous Resistance............................................................................................................75 Assessing Endogenous Resistance Potential .........................................................................................................76 Fitness of Resistant Mutants and Compensatory Mutations.............................................................................77 TARGETS ......................................................................................................................................................................78 Linking MIC to Target Inhibition..........................................................................................................................78 Support for Enzyme Inhibition as the Antibacterial Mechanism......................................................................78 SAR of enzyme inhibition and MIC...................................................................................................................78 Phenotypic profiling..............................................................................................................................................78 Under- and overexpression of the putative target............................................................................................79 An array of arrays: expression, sensitization, resistance, and synergy.........................................................79 Target alteration ...................................................................................................................................................79 RECENT RECORD OF SINGLE-ENZYME-TARGETED AGENTS ....................................................................80 The Opacity of the Discovery Process....................................................................................................................80 MurB to MurF Enzymes as Antibacterial Targets ..............................................................................................80 Targets of Inhibitors Discovered by Enzyme Screening or Design ...................................................................83 UppS .......................................................................................................................................................................83 WalK/WalR ............................................................................................................................................................83 LpxC .......................................................................................................................................................................84 FtsZ.........................................................................................................................................................................85 Inhibitors Identified after Phenotypic and Empirical Discovery .......................................................................86 Single-Enzyme Targets of Novel Inhibitors in Clinical Trials ...........................................................................86 Peptidyl deformylase ............................................................................................................................................86 Enoyl-reductases of FAS II..................................................................................................................................87 Leucyl tRNA synthetases of Gram-negative organisms...................................................................................88 RNA polymerase in C. difficile.............................................................................................................................88 DHFR and iclaprim..............................................................................................................................................89 Summary of Challenges of Single-Target Discovery............................................................................................89 MULTITARGETING....................................................................................................................................................89 Single Pharmacophore, Multiple Targets..............................................................................................................90 Dual inhibitors of DNA gyrase and topoisomerase IV....................................................................................90 Dual inhibitors of Gram-positive DNA polymerases .......................................................................................92 ␤-Ketoacyl-ACP synthases of FAS II .................................................................................................................92 Targeting Substrates and Cofactors.......................................................................................................................92 Lipid II and other specific cell wall substrates................................................................................................92 A vitamin cofactor as target................................................................................................................................93 Hybrid Molecules: Dual Pharmacophore, Multiple Targets ..............................................................................93 CHEMISTRY.................................................................................................................................................................94 Spectrum Is Due to Permeability as Well as Target Distribution.....................................................................94 Chemical Libraries Are Limiting ...........................................................................................................................95 Barriers to Intracellular Accumulation in Gram-Negative Organisms ............................................................95 Cytoplasmic and outer membranes have orthogonal sieving properties ......................................................95 RND efflux pumps.................................................................................................................................................96 Formulation of Rules for Intracellular Accumulation.........................................................................................96 Binning for SAR of antibacterials......................................................................................................................96 * Mailing address: LL Silver Consulting, LLC, 955 S. Springfield Ave., Unit C403, Springfield, NJ 07081. Phone: (973) 218-1466. E-mail: [email protected]. 71 72 SILVER CLIN.MICROBIOL.REV. Charge ....................................................................................................................................................................97 Methods for expanding the database.................................................................................................................98 Dealing with Efflux ...................................................................................................................................................98 A BRIEF PRESCRIPTION FOR NATURAL PRODUCT SCREENING..............................................................99 CONCLUSIONS ...........................................................................................................................................................99 REFERENCES ............................................................................................................................................................100 INTRODUCTION (empirical screening). Not especially innovative, but it worked. In fact, since those last discoveries in the 1980s, there has been The challenges to antibacterial discovery have kept the out- a great deal of creative, rational, technologically cutting-edge

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