Chapter 34 : The Spectrum of Drug Susceptibility in Mycobacteria

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One of the major clinical challenges facing the tuberculosis (TB) field is the fact that long durations of treatment are required to fully clear infection. Patients with drug-susceptible TB are treated with 6 to 9 months of a multidrug regimen, while treatment of drug-resistant TB, which necessitates the use of less effective drugs, can take years. The lengths of the standard antibiotic regimens for TB have been empirically determined and have evolved as new TB drugs have been developed. Thus, initial regimens (with streptomycin [SM] or SM and 4-aminosalicylic acid [PAS]) were well over a year in duration; the long duration of therapy was deemed necessary based on patients’ symptoms and long times until sputum conversion. The development of rifampin allowed the treatment course of uncomplicated, pulmonary TB to be shortened to 6 months. However, this is still substantially longer than the length of treatment required for other chronic infections; bacterial endocarditis, for example, which is considered difficult to clear, requires only 4 to 6 weeks of antibiotics.

Citation: Aldridge B, Keren I, Fortune S. 2014. The Spectrum of Drug Susceptibility in Mycobacteria, p 711-725. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0031-2013
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Figure 1

Landscape of drug susceptibility.

Citation: Aldridge B, Keren I, Fortune S. 2014. The Spectrum of Drug Susceptibility in Mycobacteria, p 711-725. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0031-2013
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Figure 2

Mycobacterial growth is asymmetric and generates diversity in growth characteristics and drug susceptibility. Time-lapse imaging of pulse-labeled . An amine-active dye (green) stains old cell wall, revealing new growth at old cell poles. Distribution of the difference in absolute elongation rate (averaged over the course of a full division cycle) in paired sister cells. In most pairs, the sister inheriting the old pole elongates faster. Schematic model of mycobacterial growth. Most of the new growth (light green) occurs from the old growing pole (red arrow). Following division, the two sister cells exhibit different growth properties. The cell inheriting the growth pole (called an “accelerator”) elongates faster and is born larger than its sister (called an “alternator”). Distribution of differential drug susceptibility in accelerator and alternator cells in individual microcolonies. Using microfluidics, microcolonies were challenged with MIC levels of antibiotics (meropenem and rifampicin shown here) and scored for survivors by their ability to elongate in recovery media. All figures were adapted from Aldridge et al. ( ).

Citation: Aldridge B, Keren I, Fortune S. 2014. The Spectrum of Drug Susceptibility in Mycobacteria, p 711-725. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0031-2013
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Figure 3

Persister cells in . Schematic representation of persister cells. Persister cell levels in a growing population of . Stationary-phase culture of was diluted 1:100, and growth and persister levels were followed over time. Persister levels were determined after 1 week of challenge with streptomycin (SM) (40 μg/ml) or ciprofloxacin (Cip) (5 µg/ml). Model explaining the need for lengthy antibiotic treatment of infection. Panels B and C were adapted from Keren et al. ( ).

Citation: Aldridge B, Keren I, Fortune S. 2014. The Spectrum of Drug Susceptibility in Mycobacteria, p 711-725. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0031-2013
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1. Wayne LG,, Hayes LG . 1996. An in vitro model for sequential study of shiftdown of Mycobacterium tuberculosis through two stages of nonreplicating persistence. Infect Immun 64 : 2062 2069.[PubMed]
2. Rustad TR,, Harrell MI,, Liao R,, Sherman DR . 2008. The enduring hypoxic response of Mycobacterium tuberculosis. PLoS One 3 : e1502. [PubMed]
3. Betts JC,, Lukey PT,, Robb LC,, McAdam RA,, Duncan K . 2002. Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol Microbiol 43 : 717 731.[PubMed][CrossRef]
4. Voskuil MI,, Schnappinger D,, Rutherford R,, Liu Y,, Schoolnik GK . 2004. Regulation of the Mycobacterium tuberculosis PE/PPE genes. Tuberculosis 84 : 256 262.[PubMed][CrossRef]
5. Bigger JW . 1944. Treatment of staphylococcal infections with penicillin. Lancet ii : 497 500.[CrossRef]
6. Keren I,, Minami S,, Rubin E,, Lewis K . 2011. Characterization and transcriptome analysis of Mycobacterium tuberculosis persisters. MBio 2 : e00100 11.[PubMed][CrossRef]
7. Keren I,, Shah D,, Spoering A,, Kaldalu N,, Lewis K . 2004. Specialized persister cells and the mechanism of multidrug tolerance in Escherichia coli. J Bacteriol 186 : 8172 8180.[PubMed][CrossRef]
8. Moyed HS,, Bertrand KP . 1983. hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. J Bacteriol 155 : 768 775.[PubMed]
9. Gill WP,, Harik NS,, Whiddon MR,, Liao RP,, Mittler JE,, Sherman DR . 2009. A replication clock for Mycobacterium tuberculosis. Nat Med 15 : 211 214.[PubMed][CrossRef]
10. Muñoz-Elías EJ,, Timm J,, Botha T,, Chan WT,, Gomez JE,, McKinney JD . 2004. Replication dynamics of Mycobacterium tuberculosis in chronically infected mice. Infect Immun 73 : 546 551.[PubMed][CrossRef]
11. de Steenwinkel JEM,, Kate ten MT,, de Knegt GJ,, Kremer K,, Aarnoutse RE,, Boeree MJ,, Verbrugh HA,, van Soolingen D,, Bakker-Woudenberg IAJM . 2012. Drug susceptibility of Mycobacterium tuberculosis Beijing genotype and association with MDR TB. Emerg Infect Dis 18 : 660 663.[PubMed][CrossRef]
12. Koul A,, Vranckx L,, Dendouga N,, Balemans W,, Van den Wyngaert I,, Vergauwen K,, Göhlmann HWH,, Willebrords R,, Poncelet A,, Guillemont J,, Bald D,, Andries K . 2008. Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis. J Biol Chem 283 : 25273 25280.[PubMed][CrossRef]
13. Wayne LG,, Sramek HA . 1994. Metronidazole is bactericidal to dormant cells of Mycobacterium tuberculosis. Antimicrob Agents Chemother 38 : 2054 2058.[PubMed][CrossRef]
14. Brooks JV,, Furney SK,, Orme IM . 1999. Metronidazole therapy in mice infected with tuberculosis. Antimicrob Agents Chemother 43 : 1285 1288.[PubMed]
15. Deb C,, Lee C-M,, Dubey VS,, Daniel J,, Abomoelak B,, Sirakova TD,, Pawar S,, Rogers L,, Kolattukudy PE . 2009. A novel in vitro multiple-stress dormancy model for Mycobacterium tuberculosis generates a lipid-loaded, drug-tolerant, dormant pathogen. PLoS One 4 : e6077. [PubMed][CrossRef]
16. Aldridge BB,, Fernandez-Suarez M,, Heller D,, Ambravaneswaran V,, Irimia D,, Toner M,, Fortune SM . 2012. Asymmetry and aging of mycobacterial cells lead to variable growth and antibiotic susceptibility. Science 335 : 100 104.[PubMed][CrossRef]
17. Wakamoto Y,, Dhar N,, Chait R,, Schneider K,, Signorino-Gelo F,, Leibler S,, McKinney JD . 2013. Dynamic persistence of antibiotic-stressed mycobacteria. Science 339 : 91 95.[PubMed][CrossRef]
18. Joyce G,, Williams KJ,, Robb M,, Noens E,, Tizzano B,, Shahrezaei V,, Robertson BD . 2012. Cell division site placement and asymmetric growth in mycobacteria. PLoS One 7 : e44582. [PubMed][CrossRef]
19. Golchin SA,, Stratford J,, Curry RJ,, McFadden J . 2012. A microfluidic system for long-term time-lapse microscopy studies of mycobacteria. Tuberculosis (Edinb) 92 : 489 496.[PubMed][CrossRef]
20. Li X-Z,, Nikaido H . 2009. Efflux-mediated drug resistance in bacteria. Drugs 69 : 1555 1623.[PubMed][CrossRef]
21. Piddock LJV . 2006. Multidrug-resistance efflux pumps—not just for resistance. Nat Rev Microbiol 4 : 629 636.[PubMed][CrossRef]
22. Li XZ,, Livermore DM,, Nikaido H . 1994. Role of efflux pump(s) in intrinsic resistance of Pseudomonas aeruginosa: resistance to tetracycline, chloramphenicol, and norfloxacin. Antimicrob Agents Chemother 38 : 1732 1741.[PubMed][CrossRef]
23. Li XZ,, Ma D,, Livermore DM,, Nikaido H . 1994. Role of efflux pump(s) in intrinsic resistance of Pseudomonas aeruginosa: active efflux as a contributing factor to beta-lactam resistance. Antimicrob Agents Chemother 38 : 1742 1752.[PubMed][CrossRef]
24. Livermore DM,, Davy KW . 1991. Invalidity for Pseudomonas aeruginosa of an accepted model of bacterial permeability to beta-lactam antibiotics. Antimicrob Agents Chemother 35 : 916 921.[PubMed][CrossRef]
25. Nikaido H . 1989. Outer membrane barrier as a mechanism of antimicrobial resistance. Antimicrob Agents Chemother 33 : 1831 1836.[PubMed][CrossRef]
26. Poole K,, Krebes K,, McNally C,, Neshat S . 1993. Multiple antibiotic resistance in Pseudomonas aeruginosa: evidence for involvement of an efflux operon. J Bacteriol 175 : 7363 7372.[PubMed]
27. Piddock LJV . 2006. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Microbiol Rev 19 : 382 402.[PubMed][CrossRef]
28. Soto SM . 2013. Role of efflux pumps in the antibiotic resistance of bacteria embedded in a biofilm. Virulence 4 : 223 229.[PubMed][CrossRef]
29. Noguchi N,, Okada H,, Narui K,, Sasatsu M . 2004. Comparison of the nucleotide sequence and expression of norA genes and microbial susceptibility in 21 strains of Staphylococcus aureus. Microb Drug Resist 10 : 197 203.[PubMed][CrossRef]
30. Kaatz GW,, Seo SM,, Ruble CA . 1993. Efflux-mediated fluoroquinolone resistance in Staphylococcus aureus. Antimicrob Agents Chemother 37 : 1086 1094.[PubMed][CrossRef]
31. Jones ME,, Boenink NM,, Verhoef J,, Kohrer K,, Schmitz FJ . 2000. Multiple mutations conferring ciprofloxacin resistance in Staphylococcus aureus demonstrate long-term stability in an antibiotic-free environment. J Antimicrob Chemother 45 : 353 356.[PubMed][CrossRef]
32. Hett EC,, Rubin EJ . 2008. Bacterial growth and cell division: a mycobacterial perspective. Microbiol Mol Biol Rev 72 : 126 156.[PubMed][CrossRef]
33. Nikaido H . 2001. Preventing drug access to targets: cell surface permeability barriers and active efflux in bacteria. Semin Cell Dev Biol 12 : 215 223.[PubMed][CrossRef]
34. Jarlier V,, Nikaido H . 1990. Permeability barrier to hydrophilic solutes in Mycobacterium chelonei. J Bacteriol 172 : 1418 1423.[PubMed]
35. Takiff HEH,, Cimino MM,, Musso MCM,, Weisbrod TT,, Martinez RR,, Delgado MBM,, Salazar LL,, Bloom BRB,, Jacobs WRW . 1996. Efflux pump of the proton antiporter family confers low-level fluoroquinolone resistance in Mycobacterium smegmatis. Proc Natl Acad Sci USA 93 : 362 366.[PubMed][CrossRef]
36. Srivastava S,, Musuka S,, Sherman C,, Meek C,, Leff R,, Gumbo T . 2010. Efflux-pump-derived multiple drug resistance to ethambutol monotherapy in Mycobacterium tuberculosis and the pharmacokinetics and pharmacodynamics of ethambutol. J Infect Dis 201 : 1225 1231.[PubMed][CrossRef]
37. Li X-ZX,, Zhang LL,, Nikaido HH . 2004. Efflux pump-mediated intrinsic drug resistance in Mycobacterium smegmatis. Antimicrob Agents Chemother 48 : 2415 2423.[PubMed][CrossRef]
38. De Rossi EE,, Aínsa JAJ,, Riccardi GG . 2006. Role of mycobacterial efflux transporters in drug resistance: an unresolved question. FEMS Microbiol Rev 30 : 36 52.[PubMed][CrossRef]
39. Danilchanka OO,, Mailaender CC,, Niederweis MM . 2008. Identification of a novel multidrug efflux pump of Mycobacterium tuberculosis. Antimicrob Agents Chemother 52 : 2503 2511.[PubMed][CrossRef]
40. Adams KN,, Takaki K,, Connolly LE,, Wiedenhoft H,, Winglee K,, Humbert O,, Edelstein PH,, Cosma CL,, Ramakrishnan L . 2011. Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell 145 : 39 53.[PubMed][CrossRef]
41. Gupta AK,, Katoch VM,, Chauhan DS,, Sharma R,, Singh M,, Venkatesan K,, Sharma VD . 2010. Microarray analysis of efflux pump genes in multidrug-resistant Mycobacterium tuberculosis during stress induced by common anti-tuberculous drugs. Microb Drug Resist 16 : 21 28.[PubMed][CrossRef]
42. Amaral L,, Martins M,, Viveiros M . 2007. Enhanced killing of intracellular multidrug-resistant Mycobacterium tuberculosis by compounds that affect the activity of efflux pumps. J Antimicrob Chemother 59 : 1237 1246.[PubMed][CrossRef]
43. Rodrigues L,, Ramos J,, Couto I,, Amaral L,, Viveiros M . 2011. Ethidium bromide transport across Mycobacterium smegmatis cell-wall: correlation with antibiotic resistance. BMC Microbiol 11 : 35. [PubMed][CrossRef]
44. Jiang X,, Zhang W,, Zhang Y,, Gao F,, Lu C,, Zhang X,, Wang H . 2008. Assessment of efflux pump gene expression in a clinical isolate Mycobacterium tuberculosis by real-time reverse transcription PCR. Microb Drug Resist 14 : 7 11.[PubMed][CrossRef]
45. Spies FS,, Almeida da Silva PE,, Ribeiro MO,, Rossetti ML,, Zaha A . 2008. Identification of mutations related to streptomycin resistance in clinical isolates of Mycobacterium tuberculosis and possible involvement of efflux mechanism. Antimicrob Agents Chemother 52 : 2947 2949.[PubMed][CrossRef]
46. Das B,, Kashino SS,, Pulu I,, Kalita D,, Swami V,, Yeger H,, Felsher DW,, Campos-Neto A . 2013. CD271(+) bone marrow mesenchymal stem cells may provide a niche for dormant Mycobacterium tuberculosis. Sci Transl Med 5 : 170ra13. [PubMed]
47. Lewis K . 2005. Persister cells and the riddle of biofilm survival. Biochemistry (Moscow) 70 : 267 274.[PubMed][CrossRef]
48. Liao J,, Schurr MJ,, Sauer K . 2013. The MerR-like regulator BrlR confers biofilm tolerance by activating multidrug efflux pumps in Pseudomonas aeruginosa biofilms. J Bacteriol 195 : 3352 3363.[PubMed][CrossRef]
49. Lopez D,, Vlamakis H,, Kolter R . 2010. Biofilms. Cold Spring Harbor Perspect Biol 2 : a000398. [PubMed][CrossRef]
50. Levin BR,, Rozen DE . 2006. Non-inherited antibiotic resistance. Nat Rev Microbiol 4 : 556 562.[PubMed][CrossRef]
51. Whiteley M,, Bangera MG,, Bumgarner RE,, Parsek MR,, Teitzel GM,, Lory S,, Greenberg EP . 2001. Gene expression in Pseudomonas aeruginosa: biofilms. Nature 413 : 860 864.[PubMed][CrossRef]
52. Veening JW,, Kuipers OP,, Brul S,, Hellingwerf KJ,, Kort R . 2006. Effects of phosphorelay perturbations on architecture, sporulation, and spore resistance in biofilms of Bacillus subtilis. J Bacteriol 188 : 3099 3109.[PubMed][CrossRef]
53. Stewart PS,, Franklin MJ . 2008. Physiological heterogeneity in biofilms. Nat Rev Microbiol 6 : 199 210.[PubMed][CrossRef]
54. Mah T-F,, Pitts B,, Pellock B,, Walker GC,, Stewart PS,, O’Toole GA . 2003. A genetic basis for Pseudomonas aeruginosa biofilm antibiotic resistance. Nature 426 : 306 310.[PubMed][CrossRef]
55. Ojha A,, Anand M,, Bhatt A,, Kremer L,, Jacobs WR Jr,, Hatfull GF . 2005. GroEL1: a dedicated chaperone involved in mycolic acid biosynthesis during biofilm formation in mycobacteria. Cell 123 : 861 873.[PubMed][CrossRef]
56. Nguyen KT,, Piastro K,, Gray TA . 2010. Mycobacterial biofilms facilitate horizontal DNA transfer between strains of Mycobacterium smegmatis. J Bacteriol 192 : 5134 5142.[PubMed][CrossRef]
57. Hall-Stoodley L,, Stoodley P . 2005. Biofilm formation and dispersal and the transmission of human pathogens. Trends Microbiol 13 : 7 10.[PubMed][CrossRef]
58. Bardouniotis EE,, Huddleston WW,, Ceri HH,, Olson MEM . 2001. Characterization of biofilm growth and biocide susceptibility testing of Mycobacterium phlei using the MBEC assay system. FEMS Microbiol Lett 203 : 263 267.[PubMed]
59. Ojha A,, Hatfull GF . 2007. The role of iron in Mycobacterium smegmatis biofilm formation: the exochelin siderophore is essential in limiting iron conditions for biofilm formation but not for planktonic growth. Mol Microbiol 66 : 468 483.[PubMed][CrossRef]
60. Schulze-Röbbecke R,, Fischeder R . 1989. Mycobacteria in biofilms. Zentralbl Hyg Umweltmed 188 : 385 390.[PubMed]
61. Tobin DM,, Vary JC,, Ray JP,, Walsh GS,, Dunstan SJ,, Bang ND,, Hagge DA,, Khadge S,, King M-C,, Hawn TR,, Moens CB,, Ramakrishnan L . 2010. The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Cell 140 : 717 730.[PubMed][CrossRef]
62. Lenaerts AJ,, Hoff D,, Aly S,, Ehlers S,, Andries K,, Cantarero L,, Orme IM,, Basaraba RJ . 2007. Location of persisting mycobacteria in a guinea pig model of tuberculosis revealed by r207910. Antimicrob Agents Chemother 51 : 3338 3345.[PubMed][CrossRef]
63. Zambrano MM,, Kolter R . 2005. Mycobacterial biofilms: a greasy way to hold it together. Cell 123 : 762 764.[PubMed][CrossRef]
64. Ojha AK,, Baughn AD,, Sambandan D,, Hsu T,, Trivelli X,, Guerardel Y,, Alahari A,, Kremer L,, Jacobs WR Jr,, Hatfull GF . 2008. Growth of Mycobacterium tuberculosis biofilms containing free mycolic acids and harbouring drug-tolerant bacteria. Mol Microbiol 69 : 164 174.[PubMed][CrossRef]
65. Asally M,, Kittisopikul M,, Rué P,, Du Y,, Hu Z,, Çağatay T,, Robinson AB,, Lu H,, Garcia-Ojalvo J,, Süel GM . 2012. Localized cell death focuses mechanical forces during 3D patterning in a biofilm. Proc Natl Acad Sci USA 109 : 18891 18896.[PubMed][CrossRef]
66. Connolly LE,, Edelstein PH,, Ramakrishnan L . 2007. Why is long-term therapy required to cure tuberculosis? PLoS Med 4 : e120. [PubMed][CrossRef]
67. Rocco A,, Kierzek AM,, McFadden J . 2013. Slow protein fluctuations explain the emergence of growth phenotypes and persistence in clonal bacterial populations. PLoS One 8 : e54272. [PubMed][CrossRef]
68. Xie Z,, Siddiqi N,, Rubin EJ . 2005. Differential antibiotic susceptibilities of starved Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother 49 : 4778 4780.[PubMed][CrossRef]
69. Ford CB,, Lin PL,, Chase MR,, Shah RR,, Iartchouk O,, Galagan J,, Mohaideen N,, Ioerger TR,, Sacchettini JC,, Lipsitch M,, Flynn JL,, Fortune SM . 2011. Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection. Nat Genet 43 : 482 486.[PubMed][CrossRef]
70. Keren I,, Kaldalu N,, Spoering A,, Wang Y,, Lewis K . 2004. Persister cells and tolerance to antimicrobials. FEMS Microbiol Lett 230 : 13 18.[PubMed][CrossRef]
71. Moker N,, Dean CR,, Tao J . Pseudomonas aeruginosa increases formation of multidrug-tolerant persister cells in response to quorum-sensing signaling molecules. J Bacteriol 192 : 1946 1955.[PubMed][CrossRef]
72. Spoering AL,, Lewis K . 2001. Biofilms and planktonic cells of Pseudomonas aeruginosa have similar resistance to killing by antimicrobials. J Bacteriol 183 : 6746 6751.[PubMed][CrossRef]
73. Slattery A,, Victorsen AH,, Brown A,, Hillman K,, Phillips GJ . 2013. Isolation of highly persistent mutants of Salmonella enterica serovar typhimurium reveals a new toxin-antitoxin module. J Bacteriol 195 : 647 657.[PubMed][CrossRef]
74. Lechner S,, Lewis K,, Bertram R . 2012. Staphylococcus aureus persisters tolerant to bactericidal antibiotics. J Mol Microbiol Biotechnol 22 : 235 244.[PubMed][CrossRef]
75. Leung V,, Levesque CM . 2012. A stress-inducible quorum-sensing peptide mediates the formation of persister cells with noninherited multidrug tolerance. J Bacteriol 194 : 2265 2274.[PubMed][CrossRef]
76. LaFleur MD,, Kumamoto CA,, Lewis K . 2006. Candida albicans biofilms produce antifungal-tolerant persister cells. Antimicrob Agents Chemother 50 : 3839 3846.[PubMed][CrossRef]
77. Moyed HS,, Bertrand KP . 1983. hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. J Bacteriol 155 : 768 775.[PubMed]
78. Moyed HS,, Broderick SH . 1986. Molecular cloning and expression of hipA, a gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. J Bacteriol 166 : 399 403.[PubMed]
79. Correia FF,, D’Onofrio A,, Rejtar T,, Li L,, Karger BL,, Makarova K,, Koonin EV,, Lewis K . 2006. Kinase activity of overexpressed HipA is required for growth arrest and multidrug tolerance in Escherichia coli. J Bacteriol 188 : 8360 8367.[PubMed][CrossRef]
80. Falla TJ,, Chopra I . 1998. Joint tolerance to beta-lactam and fluoroquinolone antibiotics in Escherichia coli results from overexpression of hipA. Antimicrob Agents Chemother 42 : 3282 3284.[PubMed]
81. Balaban NQ . 2004. Bacterial persistence as a phenotypic switch. Science 305 : 1622 1625.[PubMed][CrossRef]
82. Shah D,, Zhang Z,, Khodursky A,, Kaldalu N,, Kurg K,, Lewis K . 2006. Persisters: a distinct physiological state of E. coli. BMC Microbiol 6 : 53. [PubMed][CrossRef]
83. Wu Y,, Vulic M,, Keren I,, Lewis K . 2012. Role of oxidative stress in persister tolerance. Antimicrob Agents Chemother 56 : 4922 4926.[PubMed][CrossRef]
84. Dörr T,, Lewis K,, Vulic M . 2009. SOS response induces persistence to fluoroquinolones in Escherichia coli. PLoS Genet 5 : e1000760. [PubMed][CrossRef]
85. Keren I,, Wu Y,, Innocencio J,, Mulcahy L,, Lewis K . 2013. Killing by antibiotics does not depend on reactive oxygen species. Science 339 : 1213 1216.[PubMed][CrossRef]
86. Hooper DC . 2001. Mechanisms of action of antimicrobials: focus on fluoroquinolones. Clin Infect Dis 32( Suppl 1) : S9 S15.[PubMed][CrossRef]
87. Davis BD,, Chen LL,, Tai PC . 1986. Misread protein creates membrane channels: an essential step in the bactericidal action of aminoglycosides. Proc Natl Acad Sci USA 83 : 6164 6168.[PubMed][CrossRef]
88. Kohanski MA,, Dwyer DJ,, Wierzbowski J,, Cottarel G,, Collins JJ . 2008. Mistranslation of membrane proteins and two-component system activation trigger antibiotic-mediated cell death. Cell 135 : 679 690.[PubMed][CrossRef]
89. Bayles KW . 2007. The biological role of death and lysis in biofilm development. Nat Rev Microbiol 5 : 721 726.[PubMed][CrossRef]
90. Uehara T,, Dinh T,, Bernhardt TG . 2009. LytM-domain factors are required for daughter cell separation and rapid ampicillin-induced lysis in Escherichia coli. J Bacteriol 191 : 5094 5107.[PubMed][CrossRef]
91. Lewis K . 2010. Persister cells. Annu Rev Microbiol 64 : 357 372.[PubMed][CrossRef]
92. Ogura T,, Hiraga S . 1983. Mini-F plasmid genes that couple host cell division to plasmid proliferation. Proc Natl Acad Sci USA 80 : 4784 4788.[PubMed][CrossRef]
93. Gerdes K,, Bech FW,, Jorgensen ST,, Løbner-Olesen A,, Rasmussen PB,, Atlung T,, Boe L,, Karlstrom O,, Molin S,, von Meyenburg K . 1986. Mechanism of postsegregational killing by the hok gene product of the parB system of plasmid R1 and its homology with the relF gene product of the E. colirelB operon. EMBO J 5 : 2023 2029.[PubMed]
94. Gerdes K,, Rasmussen PB,, Molin S . 1986. Unique type of plasmid maintenance function: postsegregational killing of plasmid-free cells. Proc Natl Acad Sci USA, 83 : 3116 3120.[PubMed][CrossRef]
95. Greenfield TJ,, Ehli E,, Kirshenmann T,, Franch T,, Gerdes K,, Weaver KE . 2000. The antisense RNA of the par locus of pAD1 regulates the expression of a 33-amino-acid toxic peptide by an unusual mechanism. Mol Microbiol 37 : 652 660.[PubMed][CrossRef]
96. Gerdes K,, Christensen SK,, Løbner-Olesen A . 2005. Prokaryotic toxin-antitoxin stress response loci. Nat Rev Microbiol 3 : 371 382.[PubMed][CrossRef]
97. Pandey DP,, Gerdes K . 2005. Toxin-antitoxin loci are highly abundant in free-living but lost from host-associated prokaryotes. Nucleic Acids Res 33 : 966 976.[PubMed][CrossRef]
98. Lewis K . 2000. Programmed death in bacteria. Microbiol Mol Biol Rev 64 : 503 514.[PubMed][CrossRef]
99. Hansen S,, Vulic M,, Min J,, Yen TJ,, Schumacher MA,, Brennan RG,, Lewis K . 2012. Regulation of the Escherichia coli HipBA toxin-antitoxin system by proteolysis. PLoS One 7 : e39185. [PubMed][CrossRef]
100. Black DS,, Irwin B,, Moyed HS . 1994. Autoregulation of hip, an operon that affects lethality due to inhibition of peptidoglycan or DNA synthesis. J Bacteriol 176 : 4081 4091.[PubMed]
101. Schumacher MA,, Piro KM,, Xu W,, Hansen S,, Lewis K,, Brennan RG . 2009. Molecular mechanisms of HipA-mediated multidrug tolerance and its neutralization by HipB. Science 323 : 396 401.[PubMed][CrossRef]
102. Black DS,, Kelly AJ,, Mardis MJ,, Moyed HS . 1991. Structure and organization of hip, an operon that affects lethality due to inhibition of peptidoglycan or DNA synthesis. J Bacteriol 173 : 5732 5739.[PubMed]
103. Maisonneuve E,, Shakespeare LJ,, Jorgensen MG,, Gerdes K . 2011. Bacterial persistence by RNA endonucleases. Proc Natl Acad Sci USA 108 : 13206 13211.[PubMed][CrossRef]
104. Spoering A,, Vulic M,, Lewis K . 2006. GlpD and PlsB participate in persister cell formation in Escherichia coli. J Bacteriol 188 : 5136 5144.[PubMed][CrossRef]
105. Girgis HS,, Harris K,, Tavazoie S . 2012. Large mutational target size for rapid emergence of bacterial persistence. Proc Natl Acad Sci USA 109 : 12740 12745.[PubMed][CrossRef]
106. Li Y,, Zhang Y . 2007. PhoU is a persistence switch involved in persister formation and tolerance to multiple antibiotics and stresses in Escherichia coli. Antimicrob Agents Chemother 51 : 2092 2099.[PubMed][CrossRef]
107. Hansen S,, Lewis K,, Vulic M . 2008. Role of global regulators and nucleotide metabolism in antibiotic tolerance in Escherichia coli. Antimicrob Agents Chemother 52 : 2718 2726.[PubMed][CrossRef]
108. Murakami K,, Ono T,, Viducic D,, Kayama S,, Mori M,, Hirota K,, Nemoto K,, Miyake Y . 2005. Role for rpoS gene of Pseudomonas aeruginosa in antibiotic tolerance. FEMS Microbiol Lett 242 : 161 167.[PubMed][CrossRef]
109. Viducic D,, Ono T,, Murakami K,, Susilowati H,, Kayama S,, Hirota K,, Miyake Y . 2006. Functional analysis of spoT, relA and dksA genes on quinolone tolerance in Pseudomonas aeruginosa under nongrowing condition. Microbiol Immunol 50 : 349 357.[PubMed][CrossRef]
110. Johnson PJ,, Levin BR . 2013. Pharmacodynamics, population dynamics, and the evolution of persistence in Staphylococcus aureus. PLoS Genet 9 : e1003123. [PubMed][CrossRef]
111. McCune RM,, McDermott W,, Tompsett R . 1956. The fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. II. The conversion of tuberculous infection to the latent state by the administration of pyrazinamide and a companion drug. J Exp Med 104 : 763 802.[PubMed][CrossRef]
112. Ahmad Z,, Klinkenberg LG,, Pinn ML . 2009. Biphasic kill curve of isoniazid reveals the presence of drug-tolerant, not drug-resistant, Mycobacterium tuberculosis in the guinea pig. J Infect Dis 200 : 1136 1143.[PubMed][CrossRef]
113. Jindani A,, Doré CJ,, Mitchison DA . 2003. Bactericidal and sterilizing activities of antituberculosis drugs during the first 14 days. Am J Respir Crit Care Med 167 : 1348 1354.[PubMed][CrossRef]
114. Lewis K . 2010. Persister cells. Annu Rev Microbiol 64 : 357 372.[PubMed][CrossRef]
115. Ramage HR,, Connolly LE,, Cox JS . 2009. Comprehensive functional analysis of Mycobacterium tuberculosis toxin-antitoxin systems: implications for pathogenesis, stress responses, and evolution. PLoS Genet 5 : e1000767. [PubMed][CrossRef]
116. Sala A,, Calderon V,, Bordes P,, Genevaux P . 2013. TAC from Mycobacterium tuberculosis: a paradigm for stress-responsive toxin-antitoxin systems controlled by SecB-like chaperones. Cell Stress Chaperones 18 : 129 135.[PubMed][CrossRef]
117. Singh R,, Barry CE 3rd,, Boshoff HI . 2010. The three RelE homologs of Mycobacterium tuberculosis have individual, drug-specific effects on bacterial antibiotic tolerance. J Bacteriol 192 : 1279 1291.[PubMed][CrossRef]
118. Barry CE 3rd,, Boshoff HI,, Dartois V,, Dick T,, Ehrt S,, Flynn J,, Schnappinger D,, Wilkinson RJ,, Young D . 2009. The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat Rev Microbiol 7 : 845 855.[PubMed]
119. Lewis K . 2001. Riddle of biofilm resistance. Antimicrob Agents Chemother 45 : 999 1007.[PubMed][CrossRef]
120. Lewis K . 2005. Persister cells and the riddle of biofilm survival. Biochemistry(Mosc) 70 : 267 274.[PubMed]

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