Abstract
Microbes portray an immense capacity to colonize their niche by sequestering all resources for themselves and producing antibiotics to thwart the growth of other microbes. Antibiotic resistance by microbes evolved to overcome this challenge. Humans have long exploited the antibiotics to control infectious diseases. This development greatly improved the global health and decreased the mortality rate, thereby increasing average life expectancy. Drug resistance also arose like natural antibiotic resistance and is accelerating at an alarming rate which poses a foreboding challenge for global health. Posttranslational modifications (PTMs) have been recognized for their role in regulating cellular dynamics. Their role in development of drug resistance seems to be hidden but fundamental. For effective drugs against infectious pathogens, it is imperative to understand the basis of drug resistance and persistence. Here, we initially discuss the mechanisms of drug resis tance in Mycobacterium and other bacterial species and eventually consider how PTMs are involved in emergence of intrinsic or adaptive drug resistance. This chapter aims to motivate the researchers in the field to dig deeper into the proteomes of pathogens to map the role of PTMs in drug resistance. A deep under standing of the roles might be the boost required for designing better antibiotics for tackling disease burden in the future.
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Andersen JL, He GX, Kakarla P, KC R, Kumar S, Lakra WS, Mukherjee MM, Ranaweera I, Shrestha U, Tran T (2015) Multidrug efflux pumps from enterobacteriaceae, Vibrio cholerae and Staphylococcus aureus bacterial food pathogens. Int J Environ Res Pub Health 12:1487–1547. doi:10.3390/ijerph120201487
Bayles KW (2014) Bacterial programmed cell death: making sense of a paradox. Nat Rev Microbiol 12:63–69. doi:10.1038/nrmicro3136
Beceiro A, Llobet E, Aranda J, Bengoechea JA, Doumith M, Hornsey M, Dhanji H, Chart H, Bou G, Livermore DM, Woodford N (2011) Phosphoethanolamine modification of lipid A in colistin-resistant variants of Acinetobacter baumannii mediated by the pmrAB two-component regulatory system. Antimicrob Agents Chemother 55:3370–3379. doi:10.1128/AAC.00079-11
Bhatt A, Molle V, Besra GS, Jacobs WR Jr, Kremer L (2007) The Mycobacterium tuberculosis FAS-II condensing enzymes: their role in mycolic acid biosynthesis, acid-fastness, pathogenesis and in future drug development. Mol Microbiol 64:1442–1454. doi:10.1111/j.1365-2958.2007.05761.x
Bornet C, Davin-Regli A, Bosi C, Pages JM, Bollet C (2000) Imipenem resistance of Enterobacter aerogenes mediated by outer membrane permeability. J Clin Microbiol 38:1048–1052
Brennan PJ, Nikaido H (1995) The envelope of mycobacteria. Annu Rev Biochem 64:29–63. doi:10.1146/annurev.bi.64.070195.000333
Broberg CA, Orth K (2010) Tipping the balance by manipulating post-translational modifications. Curr Opin Microbiol 13:34–40. doi:10.1016/j.mib.2009.12.004
Brodersen DE, Clemons WM Jr, Carter AP, Morgan-Warren RJ, Wimberly BT, Ramakrishnan V (2000) The structural basis for the action of the antibiotics tetracycline, pactamycin, and hygromycin B on the 30S ribosomal subunit. Cell 103:1143–1154. doi:10.1016/S0092-8674(00)00216-6
Brown-Elliott BA, Nash KA, Wallace RJ Jr (2012) Antimicrobial susceptibility testing, drug resistance mechanisms, and therapy of infections with nontuberculous mycobacteria. Clin Microbiol Rev 25:545–582. doi:10.1128/CMR.05030-11
Cai Y, Chai D, Wang R, Liang B, Bai N (2012) Colistin resistance of Acinetobacter baumannii: clinical reports, mechanisms and antimicrobial strategies. J Antimicrob Chemother 67:1607–1615. doi:10.1093/jac/dks084
Cain JA, Solis N, Cordwell SJ (2014) Beyond gene expression: the impact of protein post-translational modifications in bacteria. J Proteomics 97:265–286. doi:10.1016/j.jprot.2013.08.012
Chaba R, Raje M, Chakraborti PK (2002) Evidence that a eukaryotic-type serine/threonine protein kinase from Mycobacterium tuberculosis regulates morphological changes associated with cell division. Eur J Biochem 269:1078–1085. doi:10.1046/j.1432-1033.2002.02778.x
Chuang YM, Bandyopadhyay N, Rifat D, Rubin H, Bader JS, Karakousis PC (2015) Deficiency of the novel exopolyphosphatase Rv1026/PPX2 leads to metabolic downshift and altered cell wall permeability in Mycobacterium tuberculosis. MBio 6, e02428. doi:10.1128/mBio.02428-14
Cohen ML (2000) Changing patterns of infectious disease. Nature 406:762–767. doi:10.1038/35021206
Collins MD, Goodfellow M, Minnikin DE (1982) Fatty acid composition of some mycolic acid-containing coryneform bacteria. J Gen Microbiol 128:2503–2509. doi:10.1099/00221287-128-11-2503
Dame JB, Shapiro BM (1976) Use of polymyxin B, levallorphan, and tetracaine to isolate novel envelope mutants of Escherichia coli. J Bacteriol 127:961–972
De Smet KA, Kempsell KE, Gallagher A, Duncan K, Young DB (1999) Alteration of a single amino acid residue reverses fosfomycin resistance of recombinant MurA from Mycobacterium tuberculosis. Microbiology 145:3177–3184. doi:10.1099/00221287-145-11-3177
Depardieu F, Podglajen I, Leclercq R, Collatz E, Courvalin P (2007) Modes and modulations of antibiotic resistance gene expression. Clin Microbiol Rev 20:79–114. doi:10.1128/CMR.00015-06
Fernandez L, Hancock RE (2012) Adaptive and mutational resistance: role of porins and efflux pumps in drug resistance. Clin Microbiol Rev 25:661–681. doi:10.1128/CMR.00043-12
Fischer W, Haas R (2004) The RecA protein of Helicobacter pylori requires a posttranslational modification for full activity. J Bacteriol 186:777–784. doi:10.1128/JB.186.3.777-784.2004
Fortuin S, Tomazella GG, Nagaraj N, Sampson SL, Gey van Pittius NC, Soares NC, Wiker HG, de Souza GA, Warren RM (2015) Phosphoproteomics analysis of a clinical Mycobacterium tuberculosis Beijing isolate: expanding the mycobacterial phosphoproteome catalog. Front Microbiol 6:6. doi:10.3389/fmicb.2015.00006
Grangeasse C, Stulke J, Mijakovic I (2015) Regulatory potential of post-translational modifications in bacteria. Front Microbiol 6:500. doi:10.3389/fmicb.2015.00500
Guo L, Lim KB, Poduje CM, Daniel M, Gunn JS, Hackett M, Miller SI (1998) Lipid A acylation and bacterial resistance against vertebrate antimicrobial peptides. Cell 95:189–198. doi:10.1016/S0092-8674(00)81750-X
Hastings PJ, Rosenberg SM, Slack A (2004) Antibiotic-induced lateral transfer of antibiotic resis tance. Trends Microbiol 12:401–404. doi:10.1016/j.tim.2004.07.003
Hoiby N, Bjarnsholt T, Givskov M, Molin S, Ciofu O (2010) Antibiotic resistance of bacterial biofilms. Int J Antimicrob Agents 35:322–332. doi:10.1016/j.ijantimicag.2009.12.011
Huc E, Meniche X, Benz R, Bayan N, Ghazi A, Tropis M, Daffe M (2010) O-mycoloylated proteins from Corynebacterium: an unprecedented post-translational modification in bacteria. J Biol Chem 285:21908–21912. doi:10.1074/jbc.C110.133033
Hüntelmann A (2012) Making salvarsan. Experimental therapy and the development and marketing of salvarsan at the interface between science, clinic, industry and public health. In: Gaudillière J-P, Hess V (eds) Ways of regulating drugs in the 19th and 20th centuries. Palgrave Macmillan, New York, pp 43–65
Jani C, Eoh H, Lee JJ, Hamasha K, Sahana MB, Han JS, Nyayapathy S, Lee JY, Suh JW, Lee SH, Rehse SJ, Crick DC, Kang CM (2010) Regulation of polar peptidoglycan biosynthesis by Wag31 phosphorylation in mycobacteria. BMC Microbiol 10:327. doi:10.1186/1471-2180-10-327
Jarlier V, Nikaido H (1994) Mycobacterial cell wall: structure and role in natural resistance to antibiotics. FEMS Microbiol Lett 123:11–18. doi:10.1111/j.1574-6968.1994.tb07194.x
Kaatz GW, Moudgal VV, Seo SM, Kristiansen JE (2003) Phenothiazines and thioxanthenes inhibit multidrug efflux pump activity in Staphylococcus aureus. Antimicrob Agents Chemother 47:719–726. doi:10.1128/AAC.47.2.719-726.2003
Kaatz GW, Thyagarajan RV, Seo SM (2005) Effect of promoter region mutations and mgrA overexpression on transcription of norA, which encodes a Staphylococcus aureus multidrug efflux transporter. Antimicrob Agents Chemother 49:161–169. doi:10.1128/AAC.49.1.161-169.2005
Kato A, Groisman EA (2004) Connecting two-component regulatory systems by a protein that protects a response regulator from dephosphorylation by its cognate sensor. Genes Dev 18:2302–2313. doi:10.1101/gad.1230804
Kolodkin-Gal I, Engelberg-Kulka H (2009) The stationary-phase sigma factor sigma(S) is responsible for the resistance of Escherichia coli stationary-phase cells to mazEF-mediated cell death. J Bacteriol 191:3177–3182. doi:10.1128/JB.00011-09
Kornberg A, Rao NN, Ault-Riche D (1999) Inorganic polyphosphate: a molecule of many functions. Annu Rev Biochem 68:89–125. doi:10.1146/annurev.biochem.68.1.89
Koul A, Vranckx L, Dendouga N, Balemans W, Van den Wyngaert I, Vergauwen K, Gohlmann HW, 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. doi:10.1074/jbc.M803899200
Kreuzer KN (2013) DNA damage responses in prokaryotes: regulating gene expression, modulating growth patterns, and manipulating replication forks. Cold Spring Harb Perspect Biol 5:a012674. doi:10.1101/cshperspect.a012674
Lee JJ, Kan CM, Lee JH, Park KS, Jeon JH, Lee SH (2014) Phosphorylation-dependent interaction between a serine/threonine kinase PknA and a putative cell division protein Wag31 in Mycobacterium tuberculosis. New Microbiol 37:525–533
Lomovskaya O, Warren MS, Lee A, Galazzo J, Fronko R, Lee M, Blais J, Cho D, Chamberland S, Renau T (2001) Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy. Antimicrob Agents Chemother 45:105–116. doi:10.1128/AAC.45.1.105-116.2001
Long KS, Poehlsgaard J, Kehrenberg C, Schwarz S, Vester B (2006) The Cfr rRNA methyltransferase confers resistance to Phenicols, Lincosamides, Oxazolidinones, Pleuromutilins, and Streptogramin A antibiotics. Antimicrob Agents Chemother 50:2500–2505. doi:10.1128/AAC.00131-06
Moritz EM, Hergenrother PJ (2007) Toxin-antitoxin systems are ubiquitous and plasmid-encoded in vancomycin-resistant enterococci. Proc Natl Acad Sci U S A 104:311–316. doi:10.1073/pnas.0601168104
Morrissey JH, Choi SH, Smith SA (2012) Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation. Blood 119:5972–5979. doi:10.1182/blood-2012-03-306605
Moskowitz SM, Ernst RK, Miller SI (2004) PmrAB, a two-component regulatory system of Pseudomonas aeruginosa that modulates resistance to cationic antimicrobial peptides and addition of aminoarabinose to lipid A. J Bacteriol 186:575–579. doi:10.1128/JB.186.2.575-579.2004
Mutschler H, Gebhardt M, Shoeman RL, Meinhart A (2011) A novel mechanism of programmed cell death in bacteria by toxin-antitoxin systems corrupts peptidoglycan synthesis. PLoS Biol 9, e1001033. doi:10.1371/journal.pbio.1001033
Nakedi KC, Nel AJ, Garnett S, Blackburn JM, Soares NC (2015) Comparative Ser/Thr/Tyr phosphoproteomics between two mycobacterial species: the fast growing Mycobacterium smegmatis and the slow growing Mycobacterium bovis BCG. Front Microbiol 6:237. doi:10.3389/fmicb.2015.00237
Neyfakh AA, Bidnenko VE, Chen LB (1991) Efflux-mediated multidrug resistance in Bacillus subtilis: similarities and dissimilarities with the mammalian system. Proc Natl Acad Sci U S A 88:4781–4785
Neyfakh AA, Borsch CM, Kaatz GW (1993) Fluoroquinolone resistance protein NorA of Staphylococcus aureus is a multidrug efflux transporter. Antimicrob Agents Chemother 37:128–129. doi:10.1128/AAC.37.1.128
Nikaido H (2009) Multidrug resistance in bacteria. Annu Rev Biochem 78:119–146. doi:10.1146/annurev.biochem.78.082907.145923
O’Hara K, Kanda T, Ohmiya K, Ebisu T, Kono M (1989) Purification and characterization of macrolide 2′-phosphotransferase from a strain of Escherichia coli that is highly resistant to erythromycin. Antimicrob Agents Chemother 33:1354–1357
Oldfield E, Feng X (2014) Resistance-resistant antibiotics. Trends Pharmacol Sci 35:664–674. doi:10.1016/j.tips.2014.10.007
Oliveira P, Lindblad P (2011) Novel insights into the regulation of LexA in the cyanobacterium Synechocystis sp. Strain PCC 6803. J Bacteriol 193:3804–3814. doi:10.1128/JB.00289-11
Plocinski P, Arora N, Sarva K, Blaszczyk E, Qin H, Das N, Plocinska R, Ziolkiewicz M, Dziadek J, Kiran M, Gorla P, Cross TA, Madiraju M, Rajagopalan M (2012) Mycobacterium tuberculosis CwsA interacts with CrgA and Wag31, and the CrgA-CwsA complex is involved in peptidoglycan synthesis and cell shape determination. J Bacteriol 194:6398–6409. doi:10.1128/JB.01005-12
Quan S, Venter H, Dabbs ER (1997) Ribosylative inactivation of rifampin by Mycobacterium smegmatis is a principal contributor to its low susceptibility to this antibiotic. Antimicrob Agents Chemother 41:2456–2460
Rajkovic A, Erickson S, Witzky A, Branson OE, Seo J, Gafken PR, Frietas MA, Whitelegge JP, Faull KF, Navarre W, Darwin AJ, Ibba M (2015) Cyclic rhamnosylated elongation factor P establishes antibiotic resistance in Pseudomonas aeruginosa. MBio 6, e00823. doi:10.1128/mBio.00823-15
Ramisetty BC, Natarajan B, Santhosh RS (2015) mazEF-mediated programmed cell death in bacteria: “what is this?”. Crit Rev Microbiol 41:89–100. doi:10.3109/1040841X.2013.804030
Ranjit DK, Endres JL, Bayles KW (2011) Staphylococcus aureus CidA and LrgA proteins exhibit holin-like properties. J Bacteriol 193:2468–2476. doi:10.1128/JB.01545-10
Rice KC, Firek BA, Nelson JB, Yang SJ, Patton TG, Bayles KW (2003) The Staphylococcus aureus cidAB operon: evaluation of its role in regulation of murein hydrolase activity and penicillin tolerance. J Bacteriol 185:2635–2643. doi:10.1128/JB.185.8.2635-2643.2003
Sadeghifard N, Soheili S, Sekawi Z, Ghafourian S (2014) Is the mazEF toxin-antitoxin system responsible for vancomycin resistance in clinical isolates of Enterococcus faecalis? GMS Hyg Infect Control 9:Doc05. doi:10.3205/dgkh000225
Sahal G, Bilkay IS (2014) Multi drug resistance in strong biofilm forming clinical isolates of Staphylococcus epidermidis. Braz J Microbiol 45:539–544. doi:10.1590/S1517-83822014005000042
Sahal G, Nasseri B, Bilkay IS, Piskin E (2015) Anti-biofilm effect of nanometer scale silver (NmSAg) coatings on glass and polystyrene surfaces against P. mirabilis, C. glabrata and C. tropicalis strains. J Appl Biomater Funct Mater. doi:10.5301/jabfm.5000248
Saier MH Jr, Paulsen IT (2001) Phylogeny of multidrug transporters. Semin Cell Dev Biol 12:205–213. doi:10.1006/scdb.2000.0246
Sedwick C (2011) PezT: a bacterial suicide gene. PLoS Biol 9, e1001036. doi:10.1371/journal.pbio.1001036
Shaw KJ, Rather PN, Hare RS, Miller GH (1993) Molecular genetics of aminoglycoside resistance genes and familial relationships of the aminoglycoside-modifying enzymes. Microbiol Rev 57:138–163
Skarzynski T, Mistry A, Wonacott A, Hutchinson SE, Kelly VA, Duncan K (1996) Structure of UDP-N-acetylglucosamine enolpyruvyl transferase, an enzyme essential for the synthesis of bacterial peptidoglycan, complexed with substrate UDP-N-acetylglucosamine and the drug fosfomycin. Structure 4:1465–1474. doi:10.1016/S0969-2126(96)00153-0
Stallings CL, Chu L, Li LX, Glickman MS (2011) Catalytic and non-catalytic roles for the mono-ADP-ribosyltransferase Arr in the mycobacterial DNA damage response. PLoS One 6, e21807. doi:10.1371/journal.pone.0021807
Sun F, Ding Y, Ji Q, Liang Z, Deng X, Wong CCL, Yi C, Zhang L, Xie S, Alvarez S, Hicks LM, Luo C, Jiang H, Lan L, He C (2012) Protein cysteine phosphorylation of SarA/MgrA family transcriptional regulators mediates bacterial virulence and antibiotic resistance. Proc Natl Acad Sci U S A 109:15461–15466. doi:10.1073/pnas.1205952109
Sutton MD, Narumi I, Walker GC (2002) Posttranslational modification of the umuD-encoded subunit of Escherichia coli DNA polymerase V regulates its interactions with the beta processivity clamp. Proc Natl Acad Sci U S A 99:5307–5312. doi:10.1073/pnas.082322099
Szymanski CM, Burr DH, Guerry P (2002) Campylobacter protein glycosylation affects host cell interactions. Infect Immun 70:2242–2244. doi:10.1128/IAI.70.4.2242-2244.2002
Thayil SM, Morrison N, Schechter N, Rubin H, Karakousis PC (2011) The role of the novel exo polyphosphatase MT0516 in Mycobacterium tuberculosis drug tolerance and persistence. PLoS One 6, e28076. doi:10.1371/journal.pone.0028076
Trieu-Cuot P, Courvalin P (1983) Nucleotide sequence of the Streptococcus faecalis plasmid gene encoding the 3′5″-aminoglycoside phosphotransferase type III. Gene 23:331–341. doi:10.1016/0378-1119(83)90022-7
Truong-Bolduc QC, Hooper DC (2010) Phosphorylation of MgrA and its effect on expression of the NorA and NorB efflux pumps of Staphylococcus aureus. J Bacteriol 192:2525–2534. doi:10.1128/JB.00018-10
Ubukata K, Itoh-Yamashita N, Konno M (1989) Cloning and expression of the norA gene for fluoro quinolone resistance in Staphylococcus aureus. Antimicrob Agents Chemother 33:1535–1539. doi:10.1128/AAC.33.9.1535
Vaara M, Vaara T, Sarvas M (1979) Decreased binding of polymyxin by polymyxin-resistant mutants of Salmonella typhimurium. J Bacteriol 139:664–667
Wang J, Stephan R, Zurfluh K, Hachler H, Fanning S (2014) Characterization of the genetic environment of bla ESBL genes, integrons and toxin-antitoxin systems identified on large transferrable plasmids in multi-drug resistant Escherichia coli. Front Microbiol 5:716. doi:10.3389/fmicb.2014.00716
Wright GD (2005) Bacterial resistance to antibiotics: enzymatic degradation and modification. Adv Drug Deliv Rev 57:1451–1470. doi:10.1016/j.addr.2005.04.002
Wright GD (2011) Molecular mechanisms of antibiotic resistance. Chem Commun (Camb) 47:4055–4061. doi:10.1039/c0cc05111j
Xie L, Liu W, Li Q, Chen S, Xu M, Huang Q, Zeng J, Zhou M, Xie J (2015) First succinyl-proteome profiling of extensively drug-resistant Mycobacterium tuberculosis revealed involvement of succinylation in cellular physiology. J Proteome Res 14:107–119. doi:10.1021/pr500859a
Xu WX, Zhang L, Mai JT, Peng RC, Yang EZ, Peng C, Wang HH (2014) The Wag31 protein interacts with AccA3 and coordinates cell wall lipid permeability and lipophilic drug resistance in Mycobacterium smegmatis. Biochem Biophys Res Commun 448:255–260. doi:10.1016/j.bbrc.2014.04.116
Yang SJ, Rice KC, Brown RJ, Patton TG, Liou LE, Park YH, Bayles KW (2005) A LysR-type regu lator, CidR, is required for induction of the Staphylococcus aureus cidABC operon. J Bacteriol 187:5893–5900. doi:10.1128/JB.187.17.5893-5900.2005
Yarmolinsky MB (1995) Programmed cell death in bacterial populations. Science 267:836–837. doi:10.1126/science.7846528
Yazawa K, Mikami Y, Sakamoto T, Ueno Y, Morisaki N, Iwasaki S, Furihata K (1994) Inactivation of the macrolide antibiotics erythromycin, midecamycin, and rokitamycin by pathogenic Nocardia species. Antimicrob Agents Chemother 38:2197–2199. doi:10.1128/AAC.38.9.2197
Yoshida H, Bogaki M, Nakamura S, Ubukata K, Konno M (1990) Nucleotide sequence and characterization of the Staphylococcus aureus norA gene, which confers resistance to quinolones. J Bacteriol 172:6942–6949
Zgur-Bertok D (2013) DNA damage repair and bacterial pathogens. PLoS Pathog 9, e1003711. doi:10.1371/journal.ppat.1003711
Zhou Z, Ribeiro AA, Lin S, Cotter RJ, Miller SI, Raetz CR (2001) Lipid A modifications in polymyxin-resistant Salmonella typhimurium: PMRA-dependent 4-amino-4-deoxy-L-arabinose, and phosphoethanolamine incorporation. J Biol Chem 276:43111–43121. doi:10.1074/jbc.M106960200
Acknowledgment
AKY is supported by the Innovative Young Biotechnologist Award (IYBA), and MK is supported by the IYBA Junior Research Fellowship (IYBAJRF) from the Department of Biotechnology, India. SA is supported by the Senior Research Fellowship (SRF), and from the Indian Council of Medical Research (ICMR), India. AKY and SJ also acknowledge DDRC-SFC grant from the Department of Biotechnology, India.
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Kandpal, M., Aggarwal, S., Jamwal, S., Yadav, A.K. (2017). Emergence of Drug Resistance in Mycobacterium and Other Bacterial Pathogens: The Posttranslational Modification Perspective. In: Arora, G., Sajid, A., Kalia, V. (eds) Drug Resistance in Bacteria, Fungi, Malaria, and Cancer. Springer, Cham. https://doi.org/10.1007/978-3-319-48683-3_9
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