Novel approaches to developing new antibiotics for bacterial infections.
Antibiotics are an essential part of modern medicine. The emergence of antibiotic-resistant mutants among bacteria is seemingly inevitable, and results, within a few decades, in decreased efficacy and withdrawal of the antibiotic from widespread usage. The traditional answer to this problem has been to introduce new antibiotics that kill the resistant mutants. Unfortunately, after more than 50 years of success, the pharmaceutical industry is now producing too few antibiotics, particularly against Gram-negative organisms, to replace antibiotics that are no longer effective for many types of infection. This paper reviews possible new ways to discover novel antibiotics. The genomics route has proven to be target rich, but has not led to the introduction of a marketed antibiotic as yet. Non-culturable bacteria may be an alternative source of new antibiotics. Bacteriophages have been shown to be antibacterial in animals, and may find use in specific infectious diseases. Developing new antibiotics that target non-multiplying bacteria is another approach that may lead to drugs that reduce the emergence of antibiotic resistance and increase patient compliance by shortening the duration of antibiotic therapy. These new discovery routes have given rise to compounds that are in preclinical development, but, with one exception, have not yet entered clinical trials. For the time being, the majority of new antibiotics that reach the marketplace are likely to be structural analogues of existing families of antibiotics or new compounds, both natural and non-natural which are screened in a conventional way against live multiplying bacteria.
Coates
A R M
AR
Medical Microbiology, Department of Cellular and Molecular Medicine, St George's, University of London, London, UK. acoates@sgul.ac.uk <acoates@sgul.ac.uk>
Hu
Y
Y
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000235:genetics; D001424:Bacterial Infections / Q000188:drug therapy*; D001435:Bacteriophages; D016503:Drug Delivery Systems; D015195:Drug Design; D004345:Drug Industry; D024881:Drug Resistance, Bacterial; D023281:Genomics / Q000639:trends; D006801:Humans
D000900:Anti-Bacterial Agents
Bull Int Union Tuberc Lung Dis. 1991 Dec;66(4):149-56
1687507
J Appl Microbiol. 2005;98(1):7-13
15610412
J Antimicrob Chemother. 2006 Dec;58(6):1185-92
17028094
Nature. 2006 Mar 16;440(7082):303-7
16541065
Clin Infect Dis. 2004 May 1;38(9):1279-86
15127341
J Antimicrob Chemother. 2001 Feb;47(2):129-40
11157895
Sci Total Environ. 2005 Mar 1;339(1-3):1-18
15740754
Lancet Infect Dis. 2005 Feb;5(2):115-9
15680781
IDrugs. 2006 Jun;9(6):420-2
16752312
Lancet Infect Dis. 2007 Jan;7(1):68-78
17182346
Exp Biol Med (Maywood). 2006 Apr;231(4):366-77
16565432
FEMS Microbiol Lett. 1998 Jan 1;158(1):139-45
9453166
Nat Biotechnol. 2006 Dec;24(12):1497-503
17160049
Int J Antimicrob Agents. 2005 Dec;26 Suppl 3:S170-5
16543079
In Silico Biol. 2004;4(3):355-60
15724285
Toxicon. 1993 Dec;31(12):1541-9
8146867
J Bacteriol. 1999 Jan;181(2):469-76
9882660
Surgery. 2005 Jun;137(6):639-46
15933632
J Bacteriol. 2004 Jul;186(14):4665-84
15231800
Nature. 2006 Dec 21;444(7122):1027-31
17183312
Avian Dis. 2003 Oct-Dec;47(4):1399-405
14708988
FEMS Microbiol Lett. 2006 May;258(2):257-62
16640582
Appl Microbiol Biotechnol. 2007 Feb;74(2):501-10
17096121
Science. 2004 Sep 10;305(5690):1622-5
15308767
Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4107-12
11259652
Chembiochem. 2002 Mar 1;3(2-3):125-34
11921390
Biotechnol Lett. 2007 Mar;29(3):465-72
17203343
Nat Rev Drug Discov. 2007 Jan;6(1):29-40
17159923
JAMA. 1998 Feb 4;279(5):365-70
9459469
Nat Rev Drug Discov. 2002 Nov;1(11):895-910
12415249
Antimicrob Agents Chemother. 2003 Feb;47(2):653-7
12543673
Nat Rev Microbiol. 2007 Jan;5(1):48-56
17143318
Biochem Pharmacol. 2006 Mar 30;71(7):1066-72
16412986
Clin Infect Dis. 2006 Sep 1;43 Suppl 2:S43-8
16894514
Drugs R D. 2006;7(3):133-51
16752940
Theor Popul Biol. 2002 Jun;61(4):471-80
12167366
J Antimicrob Chemother. 2004 Dec;54(6):971-81
15546974
Clin Microbiol Infect. 2004 Nov;10 Suppl 4:18-22
15522036
Antimicrob Agents Chemother. 2006 Jun;50(6):2087-97
16723570
Antimicrob Agents Chemother. 2000 Jul;44(7):1825-31
10858337
Angew Chem Int Ed Engl. 2003 May 9;42(18):2010-23
12746812
Nat Biotechnol. 2006 Apr;24(4):419-20
16601725
Expert Opin Investig Drugs. 1997 Feb;6(2):151-8
15989598
Ann Pharmacother. 2004 Oct;38(10):1675-82
15340128
Biochem Pharmacol. 2006 Mar 30;71(7):1042-7
16289392
Nat Biotechnol. 2006 Dec;24(12):1508-11
17160051
Nat Biotechnol. 2006 Dec;24(12):1494-6
17160048
Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
11259830
Nat Biotechnol. 2006 Dec;24(12):1504-7
17160050
Clin Infect Dis. 2004 Sep 1;39 Suppl 3:S142-50
15546109
Mayo Clin Proc. 1987 Sep;62(9):806-20
3306181
Infect Disord Drug Targets. 2006 Jun;6(2):85-106
16789873
Trends Microbiol. 2001 Dec;9(12):611-7
11728875
Infect Dis Clin North Am. 2004 Sep;18(3):621-49, xi-
15308279
J Antimicrob Chemother. 2004 Jun;53(6):1018-32
15128723
Mol Microbiol. 2005 Jul;57(2):307-12
15978065
Curr Pharm Des. 2002;8(13):1099-118
12052222
Nature. 2006 May 18;441(7091):358-61
16710421
Biochem Pharmacol. 2006 Mar 30;71(7):1048-56
16458857
Poult Sci. 2006 Jun;85(6):960-73
16776463
Appl Environ Microbiol. 2000 Jun;66(6):2541-7
10831436
Curr Drug Targets. 2006 Jul;7(7):793-811
16842212
Drug Discov Today. 2006 Jan;11(1-2):28-34
16478688
Science. 2001 Dec 7;294(5549):2170-2
11739958
Nat Biotechnol. 2004 Jan;22(1):31-6
14704699
J Mol Biol. 2006 Nov 17;364(1):1-8
17007876
Appl Environ Microbiol. 2006 Aug;72(8):5359-66
16885287
Int J Clin Pract. 2006 Mar;60(3):370-8
16494659
Biochem Pharmacol. 2006 Mar 30;71(7):1096-102
16387281
Biochem Pharmacol. 2006 Mar 30;71(7):981-90
16290171
Am J Respir Crit Care Med. 2005 Apr 1;171(7):699-706
15709048
J Chemother. 2004 Dec;16 Suppl 6:71-82
15690687
Science. 2001 Jun 22;292(5525):2326-9
11423662
Bull World Health Organ. 2001;79(8):780-90
11545337
Curr Opin Chem Biol. 1999 Aug;3(4):384-7
10419858
Drugs. 2004;64(1):63-88
14723559
Science. 1994 Apr 15;264(5157):388-93
8153626
Adv Drug Deliv Rev. 2005 Jul 29;57(10):1528-38
15949866
Emerg Infect Dis. 2006 Feb;12(2):183-90
16494740
Scand J Infect Dis. 2000;32(4):343-56
10959641
Int J Antimicrob Agents. 2007 Jan;29(1):3-8
17137753
Nat Methods. 2007 Jan;4(1):55-61
17128268
Trends Microbiol. 2005 Jan;13(1):34-40
15639630
J Chemother. 2004 Oct;16(5):419-36
15565907
Drug Discov Today. 2005 Jul 1;10(13):927-35
15993812
Science. 1995 Jul 28;269(5223):496-512
7542800
S Afr Med J. 1982 Jul 28;62(5 Spec No):3A-4A
6979804
Res Microbiol. 2002 Jan-Feb;153(1):13-8
11881893
Biochem Pharmacol. 2006 Mar 30;71(7):901-9
16494849
Int J Antimicrob Agents. 2005 Aug;26(2):106-13
16009535
Int J Tuberc Lung Dis. 1998 Jan;2(1):10-5
9562106
PLoS Genet. 2006 Jan;2(1):e7
16415984
Curr Drug Targets Infect Disord. 2001 Aug;1(2):181-99
12455414
Methods Mol Biol. 2004;266:261-87
15148423
Science. 1999 May 21;284(5418):1318-22
10334980
Antimicrob Agents Chemother. 2005 Nov;49(11):4789-92
16251333
Antimicrob Agents Chemother. 2005 Aug;49(8):3517-9
16048972
Nat Biotechnol. 2004 Feb;22(2):185-91
14716317
Nat Biotechnol. 2006 Oct;24(10):1263-9
16998472
Chemotherapy. 1999;45 Suppl 2:26-33
10449895
Int J Antimicrob Agents. 2005 Jun;25(6):453-63
15890498
Nat Biotechnol. 2006 Dec;24(12):1521-8
17160056
Antimicrob Agents Chemother. 2001 Apr;45(4):1058-64
11257016
Nat Med. 1998 May;4(5):545-6
9585218
J Laryngol Otol. 2007 Apr;121(4):341-4
17083751
Antimicrob Agents Chemother. 2001 Mar;45(3):649-59
11181338