title: Platforms for antibiotic discovery.
abstract: The spread of resistant bacteria, leading to untreatable infections, is a major public health threat but the pace of antibiotic discovery to combat these pathogens has slowed down. Most antibiotics were originally isolated by screening soil-derived actinomycetes during the golden era of antibiotic discovery in the 1940s to 1960s. However, diminishing returns from this discovery platform led to its collapse, and efforts to create a new platform based on target-focused screening of large libraries of synthetic compounds failed, in part owing to the lack of penetration of such compounds through the bacterial envelope. This article considers strategies to re-establish viable platforms for antibiotic discovery. These include investigating untapped natural product sources such as uncultured bacteria, establishing rules of compound penetration to enable the development of synthetic antibiotics, developing species-specific antibiotics and identifying prodrugs that have the potential to eradicate dormant persisters, which are often responsible for hard-to-treat infections.
authors: Department of Biology and Antimicrobial Discovery Center, Northeastern University, Boston, Massachusetts 02115, USA. k.lewis@neu.edu
authors: Kim
authors: K
authors: Lewis
mesh_terms: D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001419:Bacteria / Q000187:drug effects; D002986:Clinical Trials as Topic; D055808:Drug Discovery / Q000191:economics / Q000639:trends*; D024881:Drug Resistance, Bacterial / Q000235:genetics; D057166:High-Throughput Screening Assays; D006801:Humans; D011355:Prodrugs; D013045:Species Specificity
chemical_list: D000900:Anti-Bacterial Agents; D011355:Prodrugs
references: Nat Biotechnol. 2004 Feb;22(2):167-8
references: 14755287
references: Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):8938-42
references: 1409590
references: Nat Rev Microbiol. 2006 Jul;4(7):556-62
references: 16778840
references: Bacteriophage. 2012 Apr 1;2(2):105-283
references: 23050221
references: Agents Actions. 1976 Jul;6(4):468-75
references: 8969
references: Appl Environ Microbiol. 2010 Apr;76(8):2445-50
references: 20173072
references: J Ind Microbiol Biotechnol. 2011 Jun;38(6):657-66
references: 21253811
references: Lancet Infect Dis. 2010 Sep;10(9):597-602
references: 20705517
references: Int J Antimicrob Agents. 2008 Jan;31(1):78-80
references: 17913472
references: Curr Microbiol. 2011 Feb;62(2):335-40
references: 20711581
references: J Antimicrob Chemother. 2010 Feb;65(2):233-8
references: 19996144
references: Antimicrob Agents Chemother. 2010 Jan;54(1):39-44
references: 19841146
references: Nature. 2011 Nov 27;480(7378):565-9
references: 22121023
references: Science. 2010 Jul 2;329(5987):52-6
references: 20488990
references: Antimicrob Agents Chemother. 2002 Feb;46(2):267-74
references: 11796329
references: Antimicrob Agents Chemother. 2006 Feb;50(2):519-26
references: 16436705
references: Methods Mol Biol. 2009;486:57-75
references: 19347616
references: Curr Protoc Bioinformatics. 2008 Jun;Chapter 14:Unit 14.6
references: 18551414
references: Med Res Rev. 1996 Jan;16(1):3-50
references: 8788213
references: Science. 2004 Sep 10;305(5690):1622-5
references: 15308767
references: J Microbiol Methods. 2008 Mar;72(3):257-62
references: 18255181
references: Nat Rev Drug Discov. 2007 Jan;6(1):29-40
references: 17159923
references: Antimicrob Agents Chemother. 2003 Dec;47(12):3799-805
references: 14638486
references: N Engl J Med. 2003 Feb 13;348(7):661-3; author reply 661-3
references: 12587575
references: Antimicrob Agents Chemother. 1986 Oct;30(4):532-5
references: 3024560
references: Nat Rev Microbiol. 2007 Jan;5(1):48-56
references: 17143318
references: Nat Rev Drug Discov. 2002 Nov;1(11):895-910
references: 12415249
references: Science. 1994 Jan 14;263(5144):227-30
references: 8284673
references: Invest New Drugs. 2012 Feb;30(1):341-9
references: 20683637
references: Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1:4554-61
references: 20847294
references: Science. 2007 Jun 22;316(5832):1759-61
references: 17588934
references: Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7173-8
references: 19342493
references: Antimicrob Agents Chemother. 2004 Aug;48(8):2838-44
references: 15273089
references: Nat Biotechnol. 2003 May;21(5):526-31
references: 12692562
references: Chem Biol. 2010 Mar 26;17(3):254-64
references: 20338517
references: Annu Rev Microbiol. 2010;64:357-72
references: 20528688
references: Proc Natl Acad Sci U S A. 1976 Dec;73(12):4474-8
references: 794878
references: J Antimicrob Chemother. 2002 May;49(5):837-40
references: 12003980
references: J Bacteriol. 2010 Dec;192(23):6191-9
references: 20935098
references: Science. 2002 May 10;296(5570):1127-9
references: 12004133
references: Science. 2003 May 9;300(5621):976-80
references: 12738864
references: PLoS Biol. 2010 Feb 23;8(2):e1000317
references: 20186264
references: J Med Chem. 1999 Dec 2;42(24):4928-31
references: 10585202
references: Nature. 2002 Oct 10;419(6907):587-93
references: 12374972
references: Science. 2005 Jan 14;307(5707):223-7
references: 15591164
references: Cell. 2011 Sep 16;146(6):855-8
references: 21907397
references: Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10414-10419
references: 16801562
references: DNA Res. 2005;12(5):291-9
references: 16769691
references: J Antibiot (Tokyo). 1976 Jun;29(6):668-9
references: 950324
references: Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
references: 11259830
references: Nat Biotechnol. 2006 Dec;24(12):1504-7
references: 17160050
references: Biochem Biophys Res Commun. 2010 May 28;396(2):440-4
references: 20433810
references: Mol Microbiol. 1999 Oct;34(1):102-11
references: 10540289
references: Eur J Clin Microbiol Infect Dis. 1989 Dec;8(12):1064-7
references: 2559846
references: J Bacteriol. 1997 Dec;179(23):7360-8
references: 9393700
references: Nature. 2009 Jan 22;457(7228):480-4
references: 19043404
references: Nature. 2006 May 18;441(7091):358-61
references: 16710421
references: J Chem Inf Model. 2005 Jan-Feb;45(1):177-82
references: 15667143
references: J Antimicrob Chemother. 2011 Jul;66(7):1417-30
references: 21558086
references: Nat Biotechnol. 2002 Apr;20(4):331
references: 11923826
references: Expert Opin Drug Discov. 2008 May;3(5):487-500
references: 23484922
references: J Antibiot (Tokyo). 1975 Oct;28(10):721-6
references: 1102508
references: PLoS Biol. 2008 May 20;6(5):e120
references: 18494559
references: Dokl Akad Nauk SSSR. 1967 Nov-Dec;177(1):232-5
references: 5622968
references: Proc Natl Acad Sci U S A. 1980 Jul;77(7):3957-61
references: 6933445
references: Appl Environ Microbiol. 2007 Oct;73(20):6386-90
references: 17720826
references: Microbiol Mol Biol Rev. 2004 Dec;68(4):686-91
references: 15590780
references: Front Biosci. 2002 Oct 01;7:d2045-57
references: 12165483
references: Nature. 2002 May 9;417(6885):141-7
references: 12000953
references: Nat Biotechnol. 2003 Feb;21(2):187-90
references: 12536216
references: Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6602-6
references: 9618458
references: Nature. 2011 Jun 15;474(7351):327-36
references: 21677749
references: Nat Prod Rep. 2004 Apr;21(2):263-77
references: 15042149
references: N Engl J Med. 2010 Jan 21;362(3):197-205
references: 20089970
references: Clin Infect Dis. 2009 Jan 1;48(1):1-12
references: 19035777
references: Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2646-51
references: 20133795
references: Antimicrob Agents Chemother. 2008 Aug;52(8):2718-26
references: 18519731
references: Nat Biotechnol. 2006 Dec;24(12):1541-50
references: 17160060
references: Science. 2009 Aug 28;325(5944):1089-93
references: 19713519
references: Science. 2010 May 14;328(5980):862-6
references: 20466924
references: Clin Otolaryngol. 2009 Aug;34(4):349-57
references: 19673983
references: Science. 2009 Jan 16;323(5912):396-401
references: 19150849
references: Antimicrob Agents Chemother. 2010 Dec;54(12):5132-8
references: 20921316
references: Science. 2005 Oct 28;310(5748):670-4
references: 16223984
references: Drugs. 2004;64(2):159-204
references: 14717618
references: Antimicrob Agents Chemother. 1994 Dec;38(12):2750-7
references: 7695257
references: J Bacteriol. 1948 Feb;55(2):153-60
references: 16561443
references: Biochem Biophys Res Commun. 1975 Mar 3;63(1):328-34
references: 1092299
references: Antimicrob Agents Chemother. 1989 Sep;33(9):1493-9
references: 2817850
references: N Engl J Med. 2009 Jun 4;360(23):2397-405
references: 19494215
references: Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1433-7
references: 10677479
references: Appl Environ Microbiol. 2002 Sep;68(9):4301-6
references: 12200279
references: Microbiology (Reading). 1998 Nov;144 ( Pt 11):3039-3047
references: 9846739
references: Cell. 2007 Mar 23;128(6):1037-50
references: 17382878
references: Antimicrob Agents Chemother. 2001 Jan;45(1):105-16
references: 11120952
references: FEMS Microbiol Lett. 2004 Jan 15;230(1):13-8
references: 14734160
references: Nature. 2001 Jun 14;411(6839):843-7
references: 11459067
references: Nature. 2002 Jan 24;415(6870):389-95
references: 11807545
references: Science. 2011 Sep 16;333(6049):1630-2
references: 21835980
references: J Bacteriol. 2004 Dec;186(24):8172-80
references: 15576765
references: Org Lett. 2005 Jun 23;7(13):2731-4
references: 15957933
references: J Med Chem. 2008 May 22;51(10):2871-8
references: 18260614
references: Clin Orthop Relat Res. 2005 Aug;(437):3-6
references: 16056018
references: Annu Rev Microbiol. 1998;52:41-79
references: 9891793
references: J Antibiot (Tokyo). 1995 Jan;48(1):67-72
references: 7868392
references: Neurogastroenterol Motil. 2011 Mar;23(3):255-64, e119
references: 21054680
references: J Ind Microbiol Biotechnol. 2010 Aug;37(8):759-72
references: 20467781
references: Can Med Assoc J. 1929 Jan;20(1):11-3
references: 20317150
references: Trends Microbiol. 2006 Sep;14(9):413-20
references: 16876996
references: Biopolymers. 1998;47(6):479-91
references: 10333739
references: Lancet Infect Dis. 2013 Mar;13(3):269-75
references: 23332713
references: Microb Biotechnol. 2011 Mar;4(2):207-15
references: 21342466
references: PLoS One. 2010 Feb 05;5(2):e9085
references: 20140211
references: BMC Microbiol. 2006 Jun 12;6:53
references: 16768798
references: Annu Rev Microbiol. 2003;57:369-94
references: 14527284
references: Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13206-11
references: 21788497