The development of antibiotic resistance is usually associated with genetic changes, either to the acquisition of resistance genes, or to mutations in elements relevant for the activity of the antibiotic. However, in some situations resistance can be achieved without any genetic alteration; this is called phenotypic resistance. Non-inherited resistance is associated to specific processes such as growth in biofilms, a stationary growth phase or persistence. These situations might occur during infection but they are not usually considered in classical susceptibility tests at the clinical microbiology laboratories. Recent work has also shown that the susceptibility to antibiotics is highly dependent on the bacterial metabolism and that global metabolic regulators can modulate this phenotype. This modulation includes situations in which bacteria can be more resistant or more susceptible to antibiotics. Understanding these processes will thus help in establishing novel therapeutic approaches based on the actual susceptibility shown by bacteria during infection, which might differ from that determined in the laboratory. In this review, we discuss different examples of phenotypic resistance and the mechanisms that regulate the crosstalk between bacterial metabolism and the susceptibility to antibiotics. Finally, information on strategies currently under development for diminishing the phenotypic resistance to antibiotics of bacterial pathogens is presented.
References
[1]
Baquero, F.; Coque, T.M. Multilevel population genetics in antibiotic resistance. FEMS Microbiol. Rev. 2011, 35, 705–706, doi:10.1111/j.1574-6976.2011.00293.x.
[2]
Martinez, J.L.; Fajardo, A.; Garmendia, L.; Hernandez, A.; Linares, J.F.; Martinez-Solano, L.; Sanchez, M.B. A global view of antibiotic resistance. FEMS Microbiol. Rev. 2009, 33, 44–65, doi:10.1111/j.1574-6976.2008.00142.x.
[3]
Martinez, J.L.; Baquero, F. Mutation frequencies and antibiotic resistance. Antimicrob. Agents Chemother. 2000, 44, 1771–1777, doi:10.1128/AAC.44.7.1771-1777.2000.
[4]
Boto, L.; Martinez, J.L. Ecological and temporal constraints in the evolution of bacterial genomes. Genes 2011, 2, 804–828, doi:10.3390/genes2040804.
[5]
Baquero, F.; Alvarez-Ortega, C.; Martinez, J.L. Ecology and evolution of antibiotic resistance. Environ. Microbiol. Reports 2009, 1, 469–476, doi:10.1111/j.1758-2229.2009.00053.x.
Liu, A.; Tran, L.; Becket, E.; Lee, K.; Chinn, L.; Park, E.; Tran, K.; Miller, J.H. Antibiotic sensitivity profiles determined with an Escherichia coli gene knockout collection: Generating an antibiotic bar code. Antimicrob. Agents Chemother. 2010, 54, 1393–1403, doi:10.1128/AAC.00906-09.
[15]
Tamae, C.; Liu, A.; Kim, K.; Sitz, D.; Hong, J.; Becket, E.; Bui, A.; Solaimani, P.; Tran, K.P.; Yang, H.; et al. Determination of antibiotic hypersensitivity among 4,000 single-gene-knockout mutants of Escherichia coli. J. Bacteriol. 2008, 190, 5981–5988, doi:10.1128/JB.01982-07.
[16]
Alvarez-Ortega, C.; Wiegand, I.; Olivares, J.; Hancock, R.E.; Martinez, J.L. Genetic determinants involved in the susceptibility of Pseudomonas aeruginosa to beta-lactam antibiotics. Antimicrob. Agents Chemother. 2010, 54, 4159–4167, doi:10.1128/AAC.00257-10.
[17]
Martinez, J.L.; Rojo, F. Metabolic regulation of antibiotic resistance. FEMS Microbiol. Rev. 2011, 35, 768–789, doi:10.1111/j.1574-6976.2011.00282.x.
[18]
Linares, J.F.; Moreno, R.; Fajardo, A.; Martinez-Solano, L.; Escalante, R.; Rojo, F.; Martinez, J.L. The global regulator Crc modulates metabolism, susceptibility to antibiotics and virulence in Pseudomonas aeruginosa. Environ. Microbiol. 2010, 12, 3196–3212, doi:10.1111/j.1462-2920.2010.02292.x.
[19]
Allison, K.R.; Brynildsen, M.P.; Collins, J.J. Metabolite-enabled eradication of bacterial persisters by aminoglycosides. Nature 2011, 473, 216–220.
[20]
Pethe, K.; Sequeira, P.C.; Agarwalla, S.; Rhee, K.; Kuhen, K.; Phong, W.Y.; Patel, V.; Beer, D.; Walker, J.R.; Duraiswamy, J.; et al. A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy. Nat. Commun. 2010, 1, 1–8.
[21]
Lee, S.W.; Foley, E.J.; Epstein, J.A. Mode of Action of penicillin: I. Bacterial growth and penicillin activity-Staphylococcus aureus FDA. J. Bacteriol. 1944, 48, 393–399.
[22]
Mc Dermott, W. Microbial persistence. Yale J. Biol. Med. 1958, 30, 257–291.
[23]
Eagle, H. The effect of the size of the inoculum and the age of the infection on the curative dose of penicillin in experimental infections with Streptococci, Pneumococci, and Treponema pallidum. J. Exp. Med. 1949, 90, 595–607, doi:10.1084/jem.90.6.595.
[24]
Bull, J.J.; Levin, B.R.; DeRouin, T.; Walker, N.; Bloch, C.A. Dynamics of success and failure in phage and antibiotic therapy in experimental infections. BMC Microbiol. 2002, 2, e35, doi:10.1186/1471-2180-2-35.
[25]
Clement, S.; Vaudaux, P.; Francois, P.; Schrenzel, J.; Huggler, E.; Kampf, S.; Chaponnier, C.; Lew, D.; Lacroix, J.S. Evidence of an intracellular reservoir in the nasal mucosa of patients with recurrent Staphylococcus aureus rhinosinusitis. J. Infect. Dis. 2005, 192, 1023–1028, doi:10.1086/432735.
[26]
Fitoussi, F.; Cohen, R.; Brami, G.; Doit, C.; Brahimi, N.; de la Rocque, F.; Bingen, E. Molecular DNA analysis for differentiation of persistence or relapse from recurrence in treatment failure of Streptococcus pyogenes pharyngitis. Eur. J. Clin. Microbiol. Infect. Dis. 1997, 16, 233–237, doi:10.1007/BF01709587.
[27]
Toman, K. Bacterial persistence in leprosy. Int. J. Lepr. Other Mycobact. Dis. 1981, 49, 205–217.
[28]
McCune, R.M., Jr.; Tompsett, R. Fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. I. The persistence of drug-susceptible tubercle bacilli in the tissues despite prolonged antimicrobial therapy. J. Exp. Med. 1956, 104, 737–762, doi:10.1084/jem.104.5.737.
[29]
Ginsberg, A.M. Drugs in development for tuberculosis. Drugs 2010, 70, 2201–2214.
[30]
Koul, A.; Arnoult, E.; Lounis, N.; Guillemont, J.; Andries, K. The challenge of new drug discovery for tuberculosis. Nature 2011, 469, 483–490.
[31]
Chao, M.C.; Rubin, E.J. Letting sleeping dos lie: Does dormancy play a role in tuberculosis? Annu. Rev. Microbiol. 2010, 64, 293–311, doi:10.1146/annurev.micro.112408.134043.
[32]
Costerton, J.W.; Stewart, P.S.; Greenberg, E.P. Bacterial biofilms: A common cause of persistent infections. Science 1999, 284, 1318–1322, doi:10.1126/science.284.5418.1318.
[33]
Hall-Stoodley, L.; Costerton, J.W.; Stoodley, P. Bacterial biofilms: From the natural environment to infectious diseases. Nat. Rev. Microbiol. 2004, 2, 95–108, doi:10.1038/nrmicro821.
[34]
Kolter, R.; Greenberg, E.P. Microbial sciences: The superficial life of microbes. Nature 2006, 441, 300–302, doi:10.1038/441300a.
[35]
Hansen, S.K.; Rainey, P.B.; Haagensen, J.A.; Molin, S. Evolution of species interactions in a biofilm community. Nature 2007, 445, 533–536.
[36]
Folkesson, A.; Haagensen, J.A.; Zampaloni, C.; Sternberg, C.; Molin, S. Biofilm induced tolerance towards antimicrobial peptides. PLoS One 2008, 3, e1891.
[37]
Fux, C.A.; Costerton, J.W.; Stewart, P.S.; Stoodley, P. Survival strategies of infectious biofilms. Trends Microbiol. 2005, 13, 34–40, doi:10.1016/j.tim.2004.11.010.
[38]
Hogan, D.; Kolter, R. Why are bacteria refractory to antimicrobials? Curr. Opin. Microbiol. 2002, 5, 472–477, doi:10.1016/S1369-5274(02)00357-0.
[39]
Lewis, K. Multidrug tolerance of biofilms and persister cells. Curr. Top. Microbiol. Immunol. 2008, 322, 107–131, doi:10.1007/978-3-540-75418-3_6.
[40]
Stewart, P.S. Mechanisms of antibiotic resistance in bacterial biofilms. Int. J. Med. Microbiol. 2002, 292, 107–113, doi:10.1078/1438-4221-00196.
[41]
Stewart, P.S.; Costerton, J.W. Antibiotic resistance of bacteria in biofilms. Lancet 2001, 358, 135–138, doi:10.1016/S0140-6736(01)05321-1.
[42]
Drenkard, E.; Ausubel, F.M. Pseudomonas biofilm formation and antibiotic resistance are linked to phenotypic variation. Nature 2002, 416, 740–743, doi:10.1038/416740a.
[43]
Davies, D. Understanding biofilm resistance to antibacterial agents. Nat. Rev. Drug Discov. 2003, 2, 114–122, doi:10.1038/nrd1008.
Corbin, A.; Pitts, B.; Parker, A.; Stewart, P.S. Antimicrobial penetration and efficacy in an in vitro oral biofilm model. Antimicrob. Agents Chemother. 2011, 55, 3338–3344, doi:10.1128/AAC.00206-11.
[48]
Singh, R.; Ray, P.; Das, A.; Sharma, M. Penetration of antibiotics through Staphylococcus aureus and Staphylococcus epidermidis biofilms. J. Antimicrob. Chemother. 2010, 65, 1955–1958, doi:10.1093/jac/dkq257.
[49]
Dong, Y.; Chen, S.; Wang, Z.; Peng, N.; Yu, J. Synergy of ultrasound microbubbles and vancomycin against Staphylococcus epidermidis biofilm. J. Antimicrob. Chemother. 2013, 68, 816–826, doi:10.1093/jac/dks490.
[50]
Walters, M.C., III; Roe, F.; Bugnicourt, A.; Franklin, M.J.; Stewart, P.S. Contributions of antibiotic penetration, oxygen limitation, and low metabolic activity to tolerance of Pseudomonas aeruginosa biofilms to ciprofloxacin and tobramycin. Antimicrob. Agents Chemother. 2003, 47, 317–323, doi:10.1128/AAC.47.1.317-323.2003.
Lewis, K. Persister cells and the riddle of biofilm survival. Biochemistry (Mosc.) 2005, 70, 267–274, doi:10.1007/s10541-005-0111-6.
[53]
Sternberg, C.; Christensen, B.B.; Johansen, T.; Toftgaard Nielsen, A.; Andersen, J.B.; Givskov, M.; Molin, S. Distribution of bacterial growth activity in flow-chamber biofilms. Appl. Environ. Microbiol. 1999, 65, 4108–4117.
[54]
Huang, C.T.; Yu, F.P.; McFeters, G.A.; Stewart, P.S. Nonuniform spatial patterns of respiratory activity within biofilms during disinfection. Appl. Environ. Microbiol. 1995, 61, 2252–2256.
[55]
Rani, S.A.; Pitts, B.; Beyenal, H.; Veluchamy, R.A.; Lewandowski, Z.; Davison, W.M.; Buckingham-Meyer, K.; Stewart, P.S. Spatial patterns of DNA replication, protein synthesis, and oxygen concentration within bacterial biofilms reveal diverse physiological states. J. Bacteriol. 2007, 189, 4223–4233, doi:10.1128/JB.00107-07.
[56]
Mulcahy, H.; Charron-Mazenod, L.; Lewenza, S. Extracellular DNA chelates cations and induces antibiotic resistance in Pseudomonas aeruginosa biofilms. PLoS Pathog. 2008, 4, e1000213.
[57]
Hoiby, N.; Bjarnsholt, T.; Givskov, M.; Molin, S.; Ciofu, O. Antibiotic resistance of bacterial biofilms. Int. J. Antimicrob. Agents 2010, 35, 322–332.
[58]
Pamp, S.J.; Gjermansen, M.; Johansen, H.K.; Tolker-Nielsen, T. Tolerance to the antimicrobial peptide colistin in Pseudomonas aeruginosa biofilms is linked to metabolically active cells, and depends on the pmr and mexAB-oprM genes. Mol. Microbiol. 2008, 68, 223–240, doi:10.1111/j.1365-2958.2008.06152.x.
[59]
Nalca, Y.; Jansch, L.; Bredenbruch, F.; Geffers, R.; Buer, J.; Haussler, S. Quorum-sensing antagonistic activities of azithromycin in Pseudomonas aeruginosa PAO1: A global approach. Antimicrob. Agents Chemother. 2006, 50, 1680–1688, doi:10.1128/AAC.50.5.1680-1688.2006.
[60]
Giamarellos-Bourboulis, E.J. Macrolides beyond the conventional antimicrobials: A class of potent immunomodulators. Int. J. Antimicrob. Agents 2008, 31, 12–20, doi:10.1016/j.ijantimicag.2007.08.001.
Fernandez, L.; Hancock, R.E. Adaptive and mutational resistance: Role of porins and efflux pumps in drug resistance. Clin. Microbiol. Rev. 2012, 25, 661–681, doi:10.1128/CMR.00043-12.
[63]
Pages, J.-M.; James, C.E.; Winterhalter, M. The porin and the permeating antibiotic: A selective diffusion barrier in Gram-negative bacteria. Nat. Rev. Microbiol. 2008, 6, 893–903, doi:10.1038/nrmicro1994.
[64]
Peterson, A.A.; Hancock, R.E.; McGroarty, E.J. Binding of polycationic antibiotics and polyamines to lipopolysaccharides of Pseudomonas aeruginosa. J. Bacteriol. 1985, 164, 1256–1261.
[65]
Macfarlane, E.L.; Kwasnicka, A.; Hancock, R.E. Role of Pseudomonas aeruginosa PhoP-phoQ in resistance to antimicrobial cationic peptides and aminoglycosides. Microbiology 2000, 146, 2543–2554.
[66]
Macfarlane, E.L.; Kwasnicka, A.; Ochs, M.M.; Hancock, R.E. PhoP-PhoQ homologues in Pseudomonas aeruginosa regulate expression of the outer-membrane protein OprH and polymyxin B resistance. Mol. Microbiol. 1999, 34, 305–316, doi:10.1046/j.1365-2958.1999.01600.x.
[67]
McPhee, J.B.; Lewenza, S.; Hancock, R.E.W. Cationic antimicrobial peptides activate a two-component regulatory system, PmrA-PmrB, that regulates resistance to polymyxin B and cationic antimicrobial peptides in Pseudomonas aeruginosa. Mol. Microbiol. 2003, 50, 205–217, doi:10.1046/j.1365-2958.2003.03673.x.
[68]
Fernández, L.; Gooderham, W.J.; Bains, M.; McPhee, J.B.; Wiegand, I.; Hancock, R.E.W. Adaptive resistance to the “last hope” antibiotics polymyxin B and colistin in Pseudomonas aeruginosa is mediated by the novel two-component regulatory system ParR-ParS. Antimicrob. Agents Chemother. 2010, 54, 3372–3382.
[69]
Groisman, E.A.; Kayser, J.; Soncini, F.C. Regulation of polymyxin resistance and adaptation to low-Mg2+ environments. J. Bacteriol. 1997, 179, 7040–7045.
[70]
Gellatly, S.L.; Needham, B.; Madera, L.; Trent, M.S.; Hancock, R.E.W. The Pseudomonas aeruginosa PhoP-PhoQ two-component regulatory system is induced upon interaction with epithelial cells and controls cytotoxicity and inflammation. Infect. Immun. 2012, 80, 3122–3131, doi:10.1128/IAI.00382-12.
[71]
Hancock, R.E.W.; Sahl, H.-G. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat. Biotechnol. 2006, 24, 1551–1557, doi:10.1038/nbt1267.
[72]
Rahmati-Bahram, A.; Magee, J.T.; Jackson, S.K. Temperature-dependent aminoglycoside resistance in Stenotrophomonas (Xanthomonas) maltophilia; alterations in protein and lipopolysaccharide with growth temperature. J. Antimicrob. Chemother. 1996, 37, 665–676, doi:10.1093/jac/37.4.665.
[73]
Manning, A.J.; Kuehn, M.J. Contribution of bacterial outer membrane vesicles to innate bacterial defense. BMC Microbiol. 2011, 11, e258, doi:10.1186/1471-2180-11-258.
[74]
Kulp, A.; Kuehn, M.J. Biological functions and biogenesis of secreted bacterial outer membrane vesicles. Ann. Rev. Microbiol. 2010, 64, 163–184, doi:10.1146/annurev.micro.091208.073413.
[75]
Mortimer, P.G.; Piddock, L.J. The accumulation of five antibacterial agents in porin-deficient mutants of Escherichia coli. J. Antimicrob. Chemother. 1993, 32, 195–213, doi:10.1093/jac/32.2.195.
[76]
Cowan, S.W.; Schirmer, T.; Rummel, G.; Steiert, M.; Ghosh, R.; Pauptit, R.A.; Jansonius, J.N.; Rosenbusch, J.P. Crystal structures explain functional properties of two E. coli porins. Nature 1992, 358, 727–733, doi:10.1038/358727a0.
[77]
Forst, S.; Delgado, J.; Inouye, M. Phosphorylation of OmpR by the osmosensor EnvZ modulates expression of the ompF and ompC genes in Escherichia coli. Proc. Natl. Acad. Sci. USA 1989, 86, 6052–6056, doi:10.1073/pnas.86.16.6052.
[78]
Yoshida, T.; Qin, L.; Egger, L.A.; Inouye, M. Transcription regulation of ompF and ompC by a single transcription factor, OmpR. J. Biol Chem 2006, 281, 17114–17123, doi:10.1074/jbc.M602112200.
[79]
Mizuno, T.; Chou, M.Y.; Inouye, M. A unique mechanism regulating gene expression: Translational inhibition by a complementary RNA transcript (micRNA). Proc. Natl. Acad. Sci. USA 1984, 81, 1966–1970, doi:10.1073/pnas.81.7.1966.
[80]
Chen, S.; Zhang, A.; Blyn, L.B.; Storz, G. MicC, a second small-RNA regulator of Omp protein expression in Escherichia coli. J. Bacteriol. 2004, 186, 6689–6697, doi:10.1128/JB.186.20.6689-6697.2004.
[81]
Takayanagi, K.; Maeda, S.; Mizuno, T. Expression of micF involved in porin synthesis in Escherichia coli: Two distinct cis-acting elements respectively regulate micF expression positively and negatively. FEMS Microbiol. Lett. 1991, 83, 39–44, doi:10.1111/j.1574-6968.1991.tb04385.x.
[82]
Delihas, N.; Forst, S. MicF: An antisense RNA gene involved in response of Escherichia coli to global stress factors. J. Mol. Biol. 2001, 313, 1–12, doi:10.1006/jmbi.2001.5029.
[83]
Pratt, L.A.; Hsing, W.; Gibson, K.E.; Silhavy, T.J. From acids to osmZ: Multiple factors influence synthesis of the OmpF and OmpC porins in Escherichia coli. Mol. Microbiol. 1996, 20, 911–917, doi:10.1111/j.1365-2958.1996.tb02532.x.
[84]
Chubiz, L.M.; Rao, C.V. Role of the mar-sox-rob regulon in regulating outer membrane porin expression. J. Bacteriol. 2011, 193, 2252–2260, doi:10.1128/JB.01382-10.
[85]
Nikaido, H.; Takatsuka, Y. Mechanisms of RND multidrug efflux pumps. Biochim. Biophys. Acta 2009, 1794, 769–781.
[86]
Nikaido, H. Multidrug resistance in bacteria. Annu. Rev. Biochem. 2009, 78, 119–146, doi:10.1146/annurev.biochem.78.082907.145923.
[87]
Li, X.Z.; Nikaido, H. Efflux-mediated drug resistance in bacteria: An update. Drugs 2009, 69, 1555–1623, doi:10.2165/11317030-000000000-00000.
[88]
Blair, J.M.; Piddock, L.J. Structure, function and inhibition of RND efflux pumps in Gram-negative bacteria: An update. Curr. Opin. Microbiol. 2009, 12, 512–519, doi:10.1016/j.mib.2009.07.003.
[89]
Piddock, L.J. Multidrug-resistance efflux pumps—Not just for resistance. Nat. Rev. Microbiol. 2006, 4, 629–636, doi:10.1038/nrmicro1464.
[90]
Martinez, J.L.; Sanchez, M.B.; Martinez-Solano, L.; Hernandez, A.; Garmendia, L.; Fajardo, A.; Alvarez-Ortega, C. Functional role of bacterial multidrug efflux pumps in microbial natural ecosystems. FEMS Microbiol. Rev. 2009, 33, 430–449, doi:10.1111/j.1574-6976.2008.00157.x.
Hernandez, A.; Ruiz, F.M.; Romero, A.; Martinez, J.L. The binding of triclosan to SmeT, the repressor of the multidrug efflux pump SmeDEF, induces antibiotic resistance in Stenotrophomonas maltophilia. PLoS Pathog. 2011, 7, e1002103.
[97]
Ma, D.; Cook, D.N.; Alberti, M.; Pon, N.G.; Nikaido, H.; Hearst, J.E. Genes acrA and acrB encode a stress-induced efflux system of Escherichia coli. Mol. Microbiol. 1995, 16, 45–55.
[98]
Lin, J.; Cagliero, C.; Guo, B.; Barton, Y.W.; Maurel, M.C.; Payot, S.; Zhang, Q. Bile salts modulate expression of the CmeABC multidrug efflux pump in Campylobacter jejuni. J. Bacteriol. 2005, 187, 7417–7424, doi:10.1128/JB.187.21.7417-7424.2005.
[99]
Nikaido, E.; Yamaguchi, A.; Nishino, K. AcrAB multidrug efflux pump regulation in Salmonella enterica serovar Typhimurium by RamA in response to environmental signals. J. Biol. Chem. 2008, 283, 24245–24253, doi:10.1074/jbc.M804544200.
[100]
Lee, E.H.; Shafer, W.M. The farAB-encoded efflux pump mediates resistance of gonococci to long-chained antibacterial fatty acids. Mol. Microbiol. 1999, 33, 839–845, doi:10.1046/j.1365-2958.1999.01530.x.
[101]
Shafer, W.M.; Qu, X.; Waring, A.J.; Lehrer, R.I. Modulation of Neisseria gonorrhoeae susceptibility to vertebrate antibacterial peptides due to a member of the resistance/nodulation/ division efflux pump family. Proc. Natl. Acad. Sci. USA 1998, 95, 1829–1833.
[102]
Poole, K. Stress responses as determinants of antimicrobial resistance in Gram-negative bacteria. Trends Microbiol. 2012, 20, 227–234, doi:10.1016/j.tim.2012.02.004.
[103]
Miller, P.F.; Sulavik, M.C. Overlaps and parallels in the regulation of intrinsic multiple-antibiotic resistance in Escherichia coli. Mol. Microbiol. 1996, 21, 441–448, doi:10.1111/j.1365-2958.1996.tb02553.x.
[104]
Chen, H.; Hu, J.; Chen, P.R.; Lan, L.; Li, Z.; Hicks, L.M.; Dinner, A.R.; He, C. The Pseudomonas aeruginosa multidrug efflux regulator MexR uses an oxidation-sensing mechanism. Proc. Natl. Acad. Sci. USA 2008, 105, 13586–13591.
[105]
Fraud, S.; Poole, K. Oxidative stress induction of the MexXY multidrug efflux genes and promotion of aminoglycoside resistance development in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2011, 55, 1068–1074, doi:10.1128/AAC.01495-10.
[106]
Fetar, H.; Gilmour, C.; Klinoski, R.; Daigle, D.M.; Dean, C.R.; Poole, K. mexEF-oprN multidrug efflux operon of Pseudomonas aeruginosa: Regulation by the MexT activator in response to nitrosative stress and chloramphenicol. Antimicrob. Agents Chemother. 2011, 55, 508–514, doi:10.1128/AAC.00830-10.
[107]
Chico-Calero, I.; Suarez, M.; Gonzalez-Zorn, B.; Scortti, M.; Slaghuis, J.; Goebel, W.; Vazquez-Boland, J.A. Hpt, a bacterial homolog of the microsomal glucose-6-phosphate translocase, mediates rapid intracellular proliferation in Listeria. Proc. Natl. Acad. Sci. USA 2002, 99, 431–436, doi:10.1073/pnas.012363899.
[108]
Kahan, F.M.; Kahan, J.S.; Cassidy, P.J.; Kropp, H. The mechanism of action of fosfomycin (phosphonomycin). Ann. NY Acad. Sci. 1974, 235, 364–386, doi:10.1111/j.1749-6632.1974.tb43277.x.
[109]
Ripio, M.T.; Brehm, K.; Lara, M.; Suarez, M.; Vazquez-Boland, J.A. Glucose-1-phosphate utilization by Listeria monocytogenes is PrfA dependent and coordinately expressed with virulence factors. J. Bacteriol. 1997, 179, 7174–7180.
[110]
Moreno, R.; Marzi, S.; Romby, P.; Rojo, F. The Crc global regulator binds to an unpaired A-rich motif at the Pseudomonas putida alkS mRNA coding sequence and inhibits translation initiation. Nucleic Acids Res. 2009, 37, 7678–7690, doi:10.1093/nar/gkp825.
[111]
Moreno, R.; Martinez-Gomariz, M.; Yuste, L.; Gil, C.; Rojo, F. The Pseudomonas putida Crc global regulator controls the hierarchical assimilation of amino acids in a complete medium: Evidence from proteomic and genomic analyses. Proteomics 2009, 9, 2910–2928, doi:10.1002/pmic.200800918.
[112]
Morales, G.; Linares, J.F.; Beloso, A.; Albar, J.P.; Martinez, J.L.; Rojo, F. The Pseudomonas putida Crc global regulator controls the expression of genes from several chromosomal catabolic pathways for aromatic compounds. J. Bacteriol. 2004, 186, 1337–1344, doi:10.1128/JB.186.5.1337-1344.2004.
[113]
MacGregor, C.H.; Wolff, J.A.; Arora, S.K.; Phibbs, P.V., Jr. Cloning of a catabolite repression control (crc) gene from Pseudomonas aeruginosa, expression of the gene in Escherichia coli, and identification of the gene product in Pseudomonas aeruginosa. J. Bacteriol. 1991, 173, 7204–7212.
Soriano, F.; Ponte, C.; Santamaria, M.; Jimenez-Arriero, M. Relevance of the inoculum effect of antibiotics in the outcome of experimental infections caused by Escherichia coli. J. Antimicrob. Chemother. 1990, 25, 621–627, doi:10.1093/jac/25.4.621.
[116]
Reguera, J.A.; Baquero, F.; Perez-Diaz, J.C.; Martinez, J.L. Factors determining resistance to beta-lactam combined with beta-lactamase inhibitors in Escherichia coli. J. Antimicrob. Chemother. 1991, 27, 569–575.
[117]
Reguera, J.A.; Baquero, F.; Perez-Diaz, J.C.; Martinez, J.L. Synergistic effect of dosage and bacterial inoculum in TEM-1 mediated antibiotic resistance. Eur. J. Clin. Microbiol. Infect. Dis. 1988, 7, 778–779, doi:10.1007/BF01975047.
[118]
Martinez, J.L.; Blazquez, J.; Baquero, F. Non-canonical mechanisms of antibiotic resistance. Eur. J. Clin. Microbiol. Infect. Dis. 1994, 13, 1015–1022, doi:10.1007/BF02111820.
[119]
Martinez, J.L.; Blazquez, J.; Vicente, M.F.; Martinez-Ferrer, M.; Reguera, J.A.; Culebras, E.; Baquero, F. Influence of gene dosing on antibiotic resistance mediated by inactivating enzymes. J. Chemother. 1989, 1, 265–266.
[120]
Udekwu, K.I.; Parrish, N.; Ankomah, P.; Baquero, F.; Levin, B.R. Functional relationship between bacterial cell density and the efficacy of antibiotics. J. Antimicrob. Chemother. 2009, 63, 745–757, doi:10.1093/jac/dkn554.
[121]
Balaban, N.Q.; Merrin, J.; Chait, R.; Kowalik, L.; Leibler, S. Bacterial persistence as a phenotypic switch. Science 2004, 305, 1622–1625, doi:10.1126/science.1099390.
Bigger, J.W. Treatment of staphylococcal infections with penicillin by intermittent sterilisation. Lancet 1944, 244, 497–500, doi:10.1016/S0140-6736(00)74210-3.
[124]
Kussell, E.; Kishony, R.; Balaban, N.Q.; Leibler, S. Bacterial persistence: A model of survival in changing environments. Genetics 2005, 169, 1807–1814, doi:10.1534/genetics.104.035352.
[125]
Balaban, N.Q. Persistence: Mechanisms for triggering and enhancing phenotypic variability. Curr. Opin. Genet. Dev. 2011, 21, 768–775, doi:10.1016/j.gde.2011.10.001.
[126]
Hansen, S.; Lewis, K.; Vulic, M. Role of global regulators and nucleotide metabolism in antibiotic tolerance in Escherichia coli. Antimicrob. Agents Chemother. 2008, 52, 2718–2726, doi:10.1128/AAC.00144-08.
Gefen, O.; Gabay, C.; Mumcuoglu, M.; Engel, G.; Balaban, N.Q. Single-cell protein induction dynamics reveals a period of vulnerability to antibiotics in persister bacteria. Proc. Natl. Acad. Sci. USA 2008, 105, 6145–6149.
[129]
Korch, S.B.; Henderson, T.A.; Hill, T.M. Characterization of the hipA7 allele of Escherichia coli and evidence that high persistence is governed by (p)ppGpp synthesis. Mol. Microbiol. 2003, 50, 1199–1213, doi:10.1046/j.1365-2958.2003.03779.x.
[130]
Rotem, E.; Loinger, A.; Ronin, I.; Levin-Reisman, I.; Gabay, C.; Shoresh, N.; Biham, O.; Balaban, N.Q. Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence. Proc. Natl. Acad. Sci. USA 2010, 107, 12541–12546, doi:10.1073/pnas.1004333107.
[131]
Keren, I.; Shah, D.; Spoering, A.; Kaldalu, N.; Lewis, K. Specialized persister cells and the mechanism of multidrug tolerance in Escherichia coli. J. Bacteriol. 2004, 186, 8172–8180, doi:10.1128/JB.186.24.8172-8180.2004.
[132]
Dorr, T.; Vulic, M.; Lewis, K. Ciprofloxacin causes persister formation by inducing the TisB toxin in Escherichia coli. PLoS Biol. 2010, 8, e1000317, doi:10.1371/journal.pbio.1000317.
[133]
Helaine, S.; Thompson, J.A.; Watson, K.G.; Liu, M.; Boyle, C.; Holden, D.W. Dynamics of intracellular bacterial replication at the single cell level. Proc. Natl. Acad. Sci. USA 2010, 107, 3746–3751.
[134]
Moker, N.; Dean, C.R.; Tao, J. Pseudomonas aeruginosa increases formation of multidrug-tolerant persister cells in response to quorum-sensing signaling molecules. J. Bacteriol. 2010, 192, 1946–1955, doi:10.1128/JB.01231-09.
[135]
Hentzer, M.; Wu, H.; Andersen, J.B.; Riedel, K.; Rasmussen, T.B.; Bagge, N.; Kumar, N.; Schembri, M.A.; Song, Z.; Kristoffersen, P.; et al. Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors. EMBO J. 2003, 22, 3803–3815, doi:10.1093/emboj/cdg366.
[136]
Wu, H.; Song, Z.; Hentzer, M.; Andersen, J.B.; Molin, S.; Givskov, M.; Hoiby, N. Synthetic furanones inhibit quorum-sensing and enhance bacterial clearance in Pseudomonas aeruginosa lung infection in mice. J. Antimicrob. Chemother. 2004, 53, 1054–1061, doi:10.1093/jac/dkh223.
[137]
Pan, J.; Bahar, A.A.; Syed, H.; Ren, D. Reverting antibiotic tolerance of Pseudomonas aeruginosa PAO1 persister cells by (Z)-4-bromo-5-(bromomethylene)-3-methylfuran-2(5H)-one. PLoS One 2012, 7, e45778.
[138]
Kim, J.S.; Heo, P.; Yang, T.J.; Lee, K.S.; Cho, D.H.; Kim, B.T.; Suh, J.H.; Lim, H.J.; Shin, D.; Kim, S.K.; et al. Selective killing of bacterial persisters by a single chemical compound without affecting normal antibiotic-sensitive cells. Antimicrob. Agents Chemother. 2011, 55, 5380–5383, doi:10.1128/AAC.00708-11.
[139]
Grant, S.S.; Kaufmann, B.B.; Chand, N.S.; Haseley, N.; Hung, D.T. Eradication of bacterial persisters with antibiotic-generated hydroxyl radicals. Proc. Natl. Acad. Sci. USA 2012, 109, 12147–12152.
[140]
Lomovskaya, O.; Bostian, K.A. Practical applications and feasibility of efflux pump inhibitors in the clinic—A vision for applied use. Biochem. Pharmacol. 2006, 71, 910–918, doi:10.1016/j.bcp.2005.12.008.
[141]
Drawz, S.M.; Bonomo, R.A. Three decades of beta-lactamase inhibitors. Clin. Microbiol. Rev. 2010, 23, 160–201, doi:10.1128/CMR.00037-09.
[142]
Martinez, J.L.; Rojo, F.; Vila, J. Are nonlethal targets useful for developing novel antimicrobials? Future Microbiol. 2011, 6, 605–607, doi:10.2217/fmb.11.47.
