title: The intrinsic resistome of bacterial pathogens.
abstract: Intrinsically resistant bacteria have emerged as a relevant health problem in the last years. Those bacterial species, several of them with an environmental origin, present naturally low-level susceptibility to several drugs. It has been proposed that intrinsic resistance is mainly the consequence of the impermeability of cellular envelopes, the activity of multidrug efflux pumps or the lack of appropriate targets for a given family of drugs. However, recently published articles indicate that the characteristic phenotype of susceptibility to antibiotics of a given bacterial species depends on the concerted activity of several elements, what has been named as intrinsic resistome. These determinants comprise not just classical resistance genes. Other elements, several of them involved in basic bacterial metabolic processes, are of relevance for the intrinsic resistance of bacterial pathogens. In the present review we analyze recent publications on the intrinsic resistomes of Escherichia coli and Pseudomonas aeruginosa. We present as well information on the role that global regulators of bacterial metabolism, as Crc from P. aeruginosa, may have on modulating bacterial susceptibility to antibiotics. Finally, we discuss the possibility of searching inhibitors of the intrinsic resistome in the aim of improving the activity of drugs currently in use for clinical practice.
authors: Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas Madrid, Spain.
authors: Jorge
authors: J
authors: Olivares
authors: Alejandra
authors: A
authors: Bernardini
authors: Guillermo
authors: G
authors: Garcia-Leon
authors: Fernando
authors: F
authors: Corona
authors: Maria
authors: M
authors: B Sanchez
authors: Jose L
authors: JL
authors: Martinez
keywords: MDR efflux pump; biofilms; intrinsic resistance; persistence; phenotypic resistance; swarming
references: Trends Microbiol. 2001 Jan;9(1):34-9
references: 11166241
references: Bioorg Med Chem. 2006 Mar 15;14(6):1993-2004
references: 16290941
references: J Biol Chem. 2009 May 22;284(21):14428-38
references: 19324881
references: Microbiol Mol Biol Rev. 1997 Sep;61(3):377-92
references: 9293187
references: Nat Rev Microbiol. 2010 Jun;8(6):423-35
references: 20440275
references: Antimicrob Agents Chemother. 2000 Jul;44(7):1771-7
references: 10858329
references: Clin Microbiol Rev. 2006 Apr;19(2):382-402
references: 16614254
references: FEBS Lett. 2012 Nov 30;586(23):4186-9
references: 23098756
references: J Bacteriol. 2008 Apr;190(8):2671-9
references: 18245294
references: Cell. 2007 Sep 7;130(5):797-810
references: 17803904
references: Genome Biol. 2007;8(9):R179
references: 17784941
references: Biochemistry. 1987 Aug 25;26(17):5471-7
references: 2823881
references: Antimicrob Agents Chemother. 1999 Jun;43(6):1340-6
references: 10348749
references: J Antimicrob Chemother. 2007 Jun;59(6):1247-60
references: 17145734
references: PLoS One. 2009 May 20;4(5):e5629
references: 19462005
references: PLoS One. 2013;8(1):e55052
references: 23383054
references: Fitoterapia. 2012 Oct;83(7):1248-55
references: 22735598
references: Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19484-9
references: 17148599
references: EMBO J. 1994 Oct 3;13(19):4684-94
references: 7925310
references: PLoS Pathog. 2008 Nov;4(11):e1000213
references: 19023416
references: J Mol Biol. 2011 Mar 11;406(5):730-44
references: 21238457
references: J Bacteriol. 2007 Jun;189(11):4223-33
references: 17337582
references: Curr Opin Microbiol. 2009 Oct;12(5):512-9
references: 19664953
references: Bioorg Med Chem. 2012 Jun 15;20(12):3915-24
references: 22579615
references: J Antimicrob Chemother. 2012 Oct;67(10):2409-17
references: 22733653
references: J Antimicrob Chemother. 1997 Sep;40(3):319-27
references: 9338482
references: J Bacteriol. 2001 Oct;183(20):5803-12
references: 11566977
references: J Biol Chem. 2009 Jan 9;284(2):945-53
references: 18955486
references: FEMS Microbiol Lett. 2005 Feb 1;243(1):117-24
references: 15668009
references: Nat Biotechnol. 2013 Feb;31(2):160-5
references: 23292609
references: J Bacteriol. 2008 Mar;190(6):1857-65
references: 18178733
references: Science. 2004 Sep 10;305(5690):1622-5
references: 15308767
references: Can J Microbiol. 2011 Oct;57(10):820-8
references: 21942332
references: Antimicrob Agents Chemother. 1998 Jun;42(6):1323-8
references: 9624468
references: Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2833-8
references: 16477005
references: Bacteriol Rev. 1963 Mar;27:87-115
references: 13999115
references: Antimicrob Agents Chemother. 2000 Nov;44(11):3079-86
references: 11036026
references: Bioorg Med Chem Lett. 2004 Jan 19;14(2):475-9
references: 14698185
references: J Bacteriol. 1993 Oct;175(19):6299-313
references: 8407802
references: Res Microbiol. 2012 Sep-Oct;163(8):550-6
references: 22910283
references: J Bacteriol. 1991 Nov;173(22):7204-12
references: 1657883
references: J Biol Chem. 1992 Feb 5;267(4):2507-11
references: 1370823
references: Mol Microbiol. 2003 Jun;48(6):1609-19
references: 12791142
references: J Antimicrob Chemother. 2013 May;68(5):1183-92
references: 23391714
references: Antimicrob Agents Chemother. 2012 Nov;56(11):5678-86
references: 22908166
references: Science. 1994 Apr 15;264(5157):382-8
references: 8153625
references: Appl Environ Microbiol. 1995 Jun;61(6):2252-6
references: 7793945
references: Mol Syst Biol. 2006;2:2006.0008
references: 16738554
references: Biochem J. 1978 Jan 1;169(1):197-204
references: 415738
references: J Antimicrob Chemother. 2013 Jan;68(1):51-9
references: 22977158
references: Antimicrob Agents Chemother. 2011 May;55(5):1874-82
references: 21357290
references: Int J Med Microbiol. 2006 Apr;296(2-3):163-70
references: 16503195
references: Antimicrob Agents Chemother. 2012 Sep;56(9):4922-6
references: 22777047
references: Antimicrob Agents Chemother. 2012 Mar;56(3):1606-8
references: 22214778
references: Annu Rev Microbiol. 1984;38:237-64
references: 6093683
references: Annu Rev Microbiol. 2010;64:357-72
references: 20528688
references: Mol Microbiol. 2005 Jul;57(1):97-110
references: 15948952
references: Genome Res. 2005 Feb;15(2):321-9
references: 15687295
references: Nucleic Acids Res. 2009 Dec;37(22):7678-90
references: 19825982
references: Nature. 2000 Aug 17;406(6797):775-81
references: 10963607
references: Curr Opin Microbiol. 2008 Apr;11(2):161-7
references: 18373943
references: Bioorg Med Chem Lett. 2003 Dec 15;13(24):4489-92
references: 14643353
references: Clin Microbiol Rev. 2002 Oct;15(4):647-79
references: 12364374
references: FEMS Microbiol Rev. 2009 Jan;33(1):44-65
references: 19054120
references: PLoS One. 2008 Feb 20;3(2):e1619
references: 18286176
references: Clin Infect Dis. 1998 Aug;27 Suppl 1:S32-41
references: 9710669
references: Curr Microbiol. 2013 Feb;66(2):152-61
references: 23090643
references: Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14328-33
references: 11717402
references: Int J Antimicrob Agents. 2003 Jul;22(1):48-53
references: 12842327
references: Antimicrob Agents Chemother. 2011 Aug;55(8):3649-60
references: 21576439
references: Int J Antimicrob Agents. 2009 Oct;34(4):343-6
references: 19615866
references: Bioorg Med Chem Lett. 2012 Jan 1;22(1):380-6
references: 22115595
references: Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1484-9
references: 21173244
references: Nat Rev Microbiol. 2005 May;3(5):371-82
references: 15864262
references: Eur J Clin Microbiol Infect Dis. 1994 Dec;13(12):1015-22
references: 7889962
references: Bioorg Med Chem Lett. 2012 Aug 15;22(16):5185-9
references: 22796180
references: J Mol Microbiol Biotechnol. 2001 Apr;3(2):225-36
references: 11321578
references: Clin Microbiol Rev. 2010 Jan;23(1):160-201
references: 20065329
references: PLoS Biol. 2010 Feb 23;8(2):e1000317
references: 20186264
references: Semin Cell Dev Biol. 2001 Jun;12(3):225-37
references: 11428915
references: J Med Chem. 1999 Dec 2;42(24):4928-31
references: 10585202
references: Annu Rev Genet. 1997;31:1-31
references: 9442888
references: Nat Biotechnol. 2013 Feb;31(2):120-2
references: 23392510
references: Antimicrob Agents Chemother. 2012 May;56(5):2237-40
references: 22330927
references: Nat Rev Microbiol. 2006 Jul;4(7):556-62
references: 16778840
references: Cell. 2003 Mar 21;112(6):741-4
references: 12654241
references: Curr Opin Microbiol. 2011 Oct;14(5):550-5
references: 21840248
references: J Bacteriol. 2006 Dec;188(24):8360-7
references: 17041039
references: Nat Rev Microbiol. 2010 Apr;8(4):251-9
references: 20190823
references: Antimicrob Agents Chemother. 2012 Jul;56(7):3753-7
references: 22526311
references: J Antimicrob Chemother. 2003 Apr;51(4):1042-5
references: 12654744
references: Curr Drug Targets. 2006 Jul;7(7):843-7
references: 16842215
references: Bioorg Med Chem Lett. 2003 Dec 1;13(23):4241-4
references: 14623009
references: Antimicrob Agents Chemother. 2003 Jan;47(1):317-23
references: 12499208
references: FEMS Microbiol Rev. 1990 Mar;6(1):45-56
references: 2186760
references: Nat Rev Microbiol. 2007 Dec;5(12):958-65
references: 18007678
references: J Antimicrob Chemother. 2003 Jan;51(1):9-11
references: 12493781
references: Chem Biol Drug Des. 2012 Oct;80(4):500-15
references: 22738437
references: J Antimicrob Chemother. 2010 Sep;65(9):1955-8
references: 20615927
references: Antimicrob Agents Chemother. 2002 Oct;46(10):3133-41
references: 12234835
references: PLoS Pathog. 2011 Jun;7(6):e1002103
references: 21738470
references: J Biol Chem. 2003 Feb 14;278(7):4524-30
references: 12435732
references: Bioorg Med Chem. 2012 Apr 15;20(8):2701-6
references: 22459211
references: Antimicrob Agents Chemother. 2011 Apr;55(4):1510-9
references: 21245441
references: PLoS Pathog. 2011 Oct;7(10):e1002298
references: 22028649
references: Nat Biotechnol. 2006 Dec;24(12):1504-7
references: 17160050
references: Annu Rev Biochem. 2009;78:119-46
references: 19231985
references: J Bacteriol. 2001 Oct;183(19):5639-44
references: 11544226
references: Environ Microbiol. 2009 Dec;11(12):2970-88
references: 19601960
references: Nat Genet. 2011 Dec 18;44(1):101-5
references: 22179135
references: Plant Physiol. 2004 Jan;134(1):320-31
references: 14701912
references: FEMS Microbiol Rev. 2011 Sep;35(5):768-89
references: 21645016
references: Antimicrob Agents Chemother. 1997 May;41(5):1140-2
references: 9145884
references: Front Microbiol. 2010 Dec 08;1:134
references: 21687759
references: Microb Drug Resist. 1996 Spring;2(1):155-7
references: 9158739
references: Biochem Pharmacol. 2006 Mar 30;71(7):930-40
references: 16359643
references: Antimicrob Agents Chemother. 1993 Oct;37(10):2059-63
references: 8257123
references: Clin Microbiol Rev. 2009 Jan;22(1):161-82, Table of Contents
references: 19136439
references: FEMS Microbiol Rev. 2009 Mar;33(2):430-49
references: 19207745
references: Antimicrob Agents Chemother. 2001 Jun;45(6):1879-81
references: 11353642
references: Int J Antimicrob Agents. 2008 Mar;31(3):198-208
references: 18180147
references: Antimicrob Agents Chemother. 1998 Sep;42(9):2225-31
references: 9736539
references: J Antimicrob Chemother. 1991 May;27(5):569-75
references: 1653204
references: Microbiology (Reading). 2007 Feb;153(Pt 2):474-482
references: 17259618
references: Clin Microbiol Rev. 2012 Oct;25(4):661-81
references: 23034325
references: Antimicrob Agents Chemother. 1977 May;11(5):852-7
references: 879738
references: Front Microbiol. 2013 Mar 12;4:47
references: 23487476
references: Biochem Biophys Res Commun. 2010 Jan 1;391(1):209-13
references: 19909729
references: Antimicrob Agents Chemother. 1994 Aug;38(8):1732-41
references: 7986003
references: FASEB J. 1998 Mar;12(3):265-74
references: 9506471
references: J Bacteriol. 1983 Aug;155(2):768-75
references: 6348026
references: Environ Microbiol. 2010 Dec;12(12):3196-212
references: 20626455
references: Antimicrob Agents Chemother. 1986 Mar;29(3):535-8
references: 3521490
references: Mol Microbiol. 1997 Jan;23(2):345-54
references: 9044268
references: Expert Opin Drug Discov. 2010 Aug;5(8):779-88
references: 22827799
references: Cell. 2008 Nov 14;135(4):679-90
references: 19013277
references: Antimicrob Agents Chemother. 2010 Apr;54(4):1393-403
references: 20065048
references: Curr Drug Targets. 2008 Sep;9(9):797-807
references: 18781925
references: Appl Environ Microbiol. 1999 Sep;65(9):4108-17
references: 10473423
references: Microbiol Mol Biol Rev. 2010 Sep;74(3):417-33
references: 20805405
references: Antimicrob Agents Chemother. 1999 Oct;43(10):2404-8
references: 10508015
references: Bioorg Med Chem Lett. 2004 Mar 8;14(5):1299-304
references: 14980686
references: Phytother Res. 2012 Nov;26(11):1637-43
references: 22371352
references: Microbiol Mol Biol Rev. 2007 Sep;71(3):463-76
references: 17804667
references: Microbiol Mol Biol Rev. 2002 Dec;66(4):671-701, table of contents
references: 12456787
references: Nature. 2000 Aug 31;406(6799):959-64
references: 10984043
references: Antimicrob Agents Chemother. 1989 Apr;33(4):595
references: 2658797
references: Mol Microbiol. 2002 Jul;45(2):501-10
references: 12123459
references: Annu Rev Microbiol. 2012;66:103-23
references: 22994490
references: Bioinformatics. 2005 Mar 1;21(5):617-23
references: 15501914
references: FEMS Microbiol Rev. 2011 Sep;35(5):736-55
references: 21303394
references: Mol Microbiol. 2002 Feb;43(3):629-40
references: 11929520
references: J Antimicrob Chemother. 2012 May;67(5):1138-44
references: 22311936
references: Lancet. 1987 Dec 19;2(8573):1473
references: 2892042
references: J Antimicrob Chemother. 2010 Nov;65(11):2382-95
references: 20846937
references: Antimicrob Agents Chemother. 1989 Nov;33(11):1831-6
references: 2692513
references: J Bacteriol. 2004 Mar;186(5):1337-44
references: 14973036
references: Ann Med. 2007;39(3):162-76
references: 17457715
references: J Bacteriol. 2008 Sep;190(17):5981-8
references: 18621901
references: Biochem J. 1991 May 15;276 ( Pt 1):269-70
references: 2039479
references: FEMS Microbiol Rev. 2010 Nov;34(6):1015-36
references: 20412308
references: Antimicrob Agents Chemother. 1999 Jul;43(7):1719-24
references: 10390229
references: J Bacteriol. 1995 May;177(9):2328-34
references: 7730261
references: Science. 2008 Jul 18;321(5887):365-7
references: 18635792
references: Nature. 2011 May 12;473(7346):216-20
references: 21562562
references: J Bacteriol. 1997 Apr;179(8):2512-8
references: 9098046
references: J Med Chem. 2012 Apr 12;55(7):3568-72
references: 22432682
references: Clin Microbiol Rev. 1988 Jan;1(1):109-23
references: 3060240
references: Antimicrob Agents Chemother. 2008 Aug;52(8):2718-26
references: 18519731
references: Science. 1971 Aug 27;173(3999):836-8
references: 4999114
references: J Bacteriol. 1993 Nov;175(22):7363-72
references: 8226684
references: Nucleic Acids Res. 2005 Feb 17;33(3):966-76
references: 15718296
references: Bioorg Med Chem Lett. 2009 Mar 15;19(6):1618-22
references: 19243936
references: Rev Infect Dis. 1986 Jul-Aug;8 Suppl 3:S292-304
references: 3529322
references: J Antimicrob Chemother. 2006 May;57(5):970-4
references: 16531429
references: Antimicrob Agents Chemother. 2008 Dec;52(12):4213-9
references: 18824604
references: J Nat Prod. 2012 Jul 27;75(7):1393-9
references: 22789014
references: Future Med Chem. 2012 Mar;4(3):347-59
references: 22393941
references: Int J Antimicrob Agents. 2007 Sep;30(3):242-9
references: 17644318
references: Antimicrob Agents Chemother. 2010 Oct;54(10):4159-67
references: 20679510
references: Mol Microbiol. 1995 Apr;16(1):45-55
references: 7651136
references: Antimicrob Agents Chemother. 2013 Jan;57(1):110-9
references: 23070157
references: Antimicrob Agents Chemother. 2008 Dec;52(12):4486-91
references: 18824609
references: Antimicrob Agents Chemother. 2010 Apr;54(4):1414-24
references: 20086146
references: Antimicrob Agents Chemother. 2001 Apr;45(4):1126-36
references: 11257026
references: PLoS Pathog. 2011 Jul;7(7):e1002158
references: 21811410
references: Appl Microbiol. 1974 Dec;28(6):987-91
references: 4217591
references: J Pharm Pharmacol. 1993 Jul;45(7):658-62
references: 7692035
references: Future Microbiol. 2011 Jun;6(6):605-7
references: 21707307
references: Biochem Pharmacol. 2006 Mar 30;71(7):910-8
references: 16427026
references: Mol Microbiol. 2010 Aug;77(4):830-40
references: 20545852
references: BMC Health Serv Res. 2012 May 23;12:122
references: 22621745
references: Antimicrob Agents Chemother. 2001 Jan;45(1):105-16
references: 11120952
references: Curr Opin Microbiol. 1999 Dec;2(6):630-5
references: 10607626
references: Mol Microbiol. 2004 Nov;54(3):702-14
references: 15491361
references: J Ind Microbiol Biotechnol. 2006 Jul;33(7):496-9
references: 16552582
references: Antimicrob Agents Chemother. 2011 Apr;55(4):1556-62
references: 21220532
references: Clin Microbiol Infect. 2006 May;12(5):418-25
references: 16643517
references: J Am Anim Hosp Assoc. 2002 Sep-Oct;38(5):407-13
references: 12220023
references: Bioorg Med Chem Lett. 2010 Apr 15;20(8):2622-4
references: 20299220
references: Antimicrob Agents Chemother. 2013 Jan;57(1):101-9
references: 23070156
references: Bioorg Med Chem Lett. 2004 May 17;14(10):2493-7
references: 15109639
references: Biochemistry. 2008 Nov 18;47(46):12037-46
references: 18942857
references: Mol Plant Microbe Interact. 2011 Jul;24(7):751-7
references: 21361789
references: Antimicrob Agents Chemother. 2009 Aug;53(8):3505-7
references: 19451285
references: Int J Antimicrob Agents. 2012 Jun;39(6):500-4
references: 22521766
references: Clin Microbiol Infect. 2009 Jan;15 Suppl 1:14-6
references: 19220346
references: Philos Trans R Soc Lond B Biol Sci. 2007 Jul 29;362(1483):1195-200
references: 17360275
references: Environ Microbiol. 2009 Jan;11(1):126-36
references: 18793317
references: Bioorg Med Chem. 2012 Jul 15;20(14):4514-21
references: 22682300
references: Curr Opin Struct Biol. 2011 Feb;21(1):109-18
references: 21315267
references: Antimicrob Agents Chemother. 2012 Dec;56(12):6397-9
references: 23006759
references: Curr Opin Microbiol. 1998 Oct;1(5):516-23
references: 10066525
references: Bioorg Med Chem Lett. 2012 Oct 1;22(19):6229-32
references: 22921080
references: Science. 1999 May 21;284(5418):1318-22
references: 10334980
references: Biochemistry. 2012 Jun 5;51(22):4551-7
references: 22587688
references: Antimicrob Agents Chemother. 1990 Oct;34(10):1938-43
references: 1963289
references: Antimicrob Agents Chemother. 2007 Jun;51(6):2092-9
references: 17420206
references: PLoS Genet. 2012 Jun;8(6):e1002804
references: 22761597
references: Science. 2004 Sep 10;305(5690):1578-9
references: 15361616
references: Antimicrob Agents Chemother. 2004 Sep;48(9):3621-4
references: 15328143
references: Eur J Clin Microbiol Infect Dis. 1988 Oct;7(5):621-9
references: 2973985
references: Curr Opin Pharmacol. 2011 Oct;11(5):439-45
references: 21835695
references: J Bacteriol. 2003 May;185(10):3111-7
references: 12730171
references: Clin Microbiol Rev. 2009 Oct;22(4):582-610
references: 19822890
references: Bioorg Med Chem. 2007 Nov 15;15(22):7087-97
references: 17869116
references: Appl Microbiol. 1972 Dec;24(6):864-70
references: 4631101
references: Bioorg Med Chem. 2006 Dec 15;14(24):8506-18
references: 16979895
references: Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13206-11
references: 21788497