Bacterial diseases

Hol, W. G. J.; Verlinde, C. L. M. J.

doi:10.1107/97809553602060000656

International
Tables for
Crystallography
Volume F
Crystallography of biological macromolecules
Edited by M. G. Rossmann and E. Arnold

pdf | chapter contents | chapter index | related articles

International Tables for Crystallography (2006). Vol. F. ch. 1.3, p. 13 | 1 | 2 |

Section 1.3.4.1.2. Bacterial diseases

W. G. J. Hol^a ^* and C. L. M. J. Verlinde^a

^aBiomolecular Structure Center, Department of Biological Structure, Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195-7742, USA
Correspondence e-mail: hol@gouda.bmsc.washington.edu

1.3.4.1.2. Bacterial diseases

| top | pdf |

A very large number of structures of important drug target proteins of bacterial origin have been solved crystallographically (Table 1.3.4.2). Currently, the most important single infectious bacterial agent is Mycobacterium tuberculosis, with three million deaths and eight million new cases annually (Murray & Salomon, 1998). The crystal structures of several M. tuberculosis potential and proven drug target proteins have been elucidated (Table 1.3.4.2). The complete M. tuberculosis genome has been sequenced recently (Cole et al., 1998), and this will undoubtedly have a tremendous impact on future drug development.

Table 1.3.4.2| top | pdf |
Protein structures of important human pathogenic bacteria

Organism	Disease(s)	Protein structures solved	Reference
Staphylococcus aureus	Abscesses	Alpha-haemolysin	[1]
	Endocarditis	Aureolysin	[2]
	Gastroenteritis	Beta-lactamase	[3]
	Toxic shock syndrome	Collagen adhesin	[4]
		7,8-Dihydroneopterin aldolase	[5]
		Dihydropteroate synthetase	[6]
		Enterotoxin A	[7]
		Enterotoxin B	[8]
		Enterotoxin C2	[9]
		Enterotoxin C3	[10]
		Exfoliative toxin A	[11]
		Ile-tRNA-synthetase	[12]
		Kanamycin nucleotidyltransferase	[13]
		Leukocidin F	[14]
		Nuclease	[15]
		Staphopain	[16]
		Staphylokinase	[17]
		Toxic shock syndrome toxin-1	[18]
Staphylococcus epidermidis	Implant infections	None
Enterococcus faecalis	Urinary tract and biliary tract infections	NADH peroxidase	[19]
(Streptococcus faecalis)		Histidine-containing phosphocarrier protein	[20]
Streptococcus mutans	Endocarditis	Glyceraldehyde-3-phosphate dehydrogenase	[21]
Streptococcus pneumoniae	Pneumonia	Penicillin-binding protein PBP2x	[22]
Streptococcus pneumoniae	Meningitis, upper respiratory tract infections	Dpnm DNA adenine methyltransferase	[23]
Streptococcus pyogenes	Pharyngitis	Inosine monophosphate dehydrogenase	[24]
Streptococcus pyogenes	Scarlet fever, toxic shock syndrome, immunologic disorders (acute glomerulonephritis and rheumatic fever)	Pyrogenic exotoxin C	[25]
Bacillus anthracis	Anthrax	Anthrax protective antigen	[26]
Bacillus cereus	Food poisoning	Beta-amylase	[27]
		Beta-lactamase II	[28]
		Neutral protease	[29]
		Oligo-1,6-glucosidase	[30]
		Phospholipase C	[31]
Clostridium botulinum	Botulism	Neurotoxin type A	[32]
Clostridium difficile	Pseudomembranous colitis	None
Clostridium perfringens	Gas gangrene	Alpha toxin	[33]
Clostridium perfringens	Food poisoning	Perfringolysin O	[34]
Clostridium tetani	Tetanus	Toxin C fragment	[35]
Corynebacterium diphtheriae	Diphtheria	Toxin	[36]
Corynebacterium diphtheriae	Diphtheria	Toxin repressor	[37]
Listeria monocytogenes	Meningitis, sepsis	Phosphatidylinositol-specific phospholipase C	[38]
Actinomyces israelii	Actinomycosis	None
Nocardia asteroides	Nocardiosis	None
Neisseria gonorrhoeae	Gonorrhea	Type 4 pilin	[39]
Neisseria gonorrhoeae	Gonorrhea	Carbonic anhydrase	[40]
Neisseria meningitidis	Meningitis	Dihydrolipoamide dehydrogenase	[41]
Bordetella pertussis	Whooping cough	Toxin	[42]
Bordetella pertussis	Whooping cough	Virulence factor P.69	[43]
Brucella sp.	Brucellosis	None
Campylobacter jejuni	Enterocolitis	None
Enterobacter cloacae	Urinary tract infection, pneumonia	Beta-lactamase: class C	[44]
Enterobacter cloacae	Urinary tract infection, pneumonia	UDP-N-acetylglucosamine enolpyruvyltransferase	[45]
Escherichia coli
ETEC (enterotoxigenic)	Traveller's diarrhoea	Heat-labile enterotoxin	[46]
ETEC (enterotoxigenic)	Traveller's diarrhoea	Heat-stable enterotoxin (is a peptide)	[47]
EHEC (enterohaemorrhagic)	HUS	Verotoxin-1	[48]
EPEC (enteropathogenic)	Diarrhoea	None
EAEC (enteroaggregative)	Diarrhoea	None
EIEC (enteroinvasive)	Diarrhoea	None
UPEC (uropathogenic)		FimH adhesin	[49]
		FimC chaperone	[49]
		PapD	[50]
NMEC (neonatal meningitis)	Meningitis	None
Franciscella tularensis	Tularemia	None
Haemophilus influenzae	Meningitis, otitis media, pneumonia	Diaminopimelate epimerase	[51]
		6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase	[52]
		Ferric iron binding protein Mirp	[53]
Klebsiella pneumoniae	Urinary tract infection, pneumonia, sepsis	β-Lactamase SHV-1	[54]
Legionella pneumophila	Pneumonia	None
Pasteurella multocida	Wound infection	None
Proteus mirabilis	Pneumonia, urinary tract infection	Catalase	[55]
Proteus mirabilis	Pneumonia, urinary tract infection	Glutathione S-transferase	[56]
Proteus vulgaris	Urinary tract infections	Pvu II DNA-(cytosine N4) methyltransferase	[57]
		Pvu II endonuclease	[58]
		Tryptophanase	[59]
Salmonella typhi	Typhoid fever	None, but many for S. typhimurium linked with zoonotic disease
Salmonella enteridis	Enterocolitis	None
Serratia marcescens	Pneumonia, urinary tract infection	Serralysin	[60]
		Aminoglycoside 3-N-acetyltransferase	[61]
		Chitinase A	[62]
		Chitobiase	[63]
		Endonuclease	[64]
		Hasa (haemophore)	[65]
		Prolyl aminopeptidase	[66]
Shigella sp.	Dysentery	Chloramphenicol acetyltransferase	[67]
Shigella sp.	Dysentery	Shiga-like toxin I	[68]
Vibrio cholerae	Cholera	Cholera toxin	[69], [70]
		DSBA oxidoreductase	[71]
		Neuraminidase	[104]
Yersinia enterocolitica	Enterocolitis	Protein-Tyr phosphatase YOPH	[72]
Yersinia pestis	Plague	None
Pseudomonas aeruginosa	Wound infection, urinary tract infection, pneumonia, sepsis	Alkaline metalloprotease	[73]
		Amidase operon	[74]
		Azurin	[75]
		Cytochrome 551	[76]
		Cytochrome c peroxidase	[77]
		Exotoxin A	[78]
		p-Hydroxybenzoate hydroxylase	[79]
		Hexapeptide xenobiotic acetyltransferase	[80]
		Mandelate racemase	[81]
		Nitrite reductase	[82]
		Ornithine transcarbamoylase	[83]
		Porphobilinogen synthase	[84]
		Pseudolysin	[85]
Burkholderia cepacia	Wound infection, urinary tract infection, pneumonia, sepsis	Biphenyl-cleaving extradiol dioxygenase	[86]
		cis-Biphenyl-2,3-dihydrodiol-2,3-dehydrogenase	[87]
		Dialkylglycine decarboxylase	[88]
		Lipase	[89]
		Phthalate dioxygenase reductase	[90]
Stenotrophomonas maltophilia (= Pseudomonas maltophilia)	Sepsis	None
Bacteroides fragilis	Intra-abdominal infections	Beta-lactamase type 2	[91]
Mycobacterium leprae	Leprosy	Chaperonin-10 (GroES homologue)	[92]
Mycobacterium leprae	Leprosy	RUVA protein	[93]
Mycobacterium tuberculosis	Tuberculosis	3-Dehydroquinate dehydratase	[94]
		Dihydrofolate reductase	[95]
		Dihydropteroate synthase	[96]
		Enoyl acyl-carrier-protein reductase (InhA)	[97]
		Mechanosensitive ion channel	[98]
		Quinolinate phosphoribosyltransferase	[99]
		Superoxide dismutase (iron dependent)	[100]
		Iron-dependent repressor
Mycobacterium bovis	Tuberculosis	Tetrahydrodipicolinate-N-succinyltransferase	[102]
Chlamydia psitacci	Psittacosis	None
Chlamydia pneumoniae	Atypical pneumonia	None
Chlamydia trahomatis	Ocular, respiratory and genital infections	None
Coxiella burnetii	Q fever	None
Rickettsia sp.	Rocky Mountain spotted fever	None
Borrelia burgdorferi	Lyme disease	Outer surface protein A	[103]
Leptospira interrogans	Leptospirosis	None
Treponema pallidum	Syphilis	None
Mycoplasma pneumoniae	Atypical pneumonia	None

References: [1] Song et al. (1996)

; [2] Banbula et al. (1998)

; [3] Herzberg & Moult (1987)

; [4] Symersky et al. (1997)

; [5] Hennig et al. (1998)

; [6] Hampele et al. (1997)

; [7] Sundstrom et al. (1996)

; [8] Papageorgiou et al. (1998)

; [9] Papageorgiou et al. (1995)

; [10] Fields et al. (1996)

; [11] Vath et al. (1997)

; [12] Silvian et al. (1999)

; [13] Pedersen et al. (1995)

; [14] Pedelacq et al. (1999)

; [15] Loll & Lattman (1989)

; [16] Hofmann et al. (1993)

; [17] Rabijns et al. (1997)

; [18] Prasad et al. (1993)

; [19] Yeh et al. (1996)

; [20] Jia et al. (1993)

; [21] Cobessi et al. (1999)

; [22] Pares et al. (1996)

; [23] Tran et al. (1998)

; [24] Zhang, Evans et al. (1999)

; [25] Roussel et al. (1997)

; [26] Petosa et al. (1997)

; [27] Mikami et al. (1999)

; [28] Carfi et al. (1995)

; [29] Pauptit et al. (1988)

; [30] Watanabe et al. (1997)

; [31] Hough et al. (1989)

; [32] Lacy et al. (1998)

; [33] Naylor et al. (1998)

; [34] Rossjohn, Feil, McKinstry et al. (1997)

; [35] Umland et al. (1997)

; [36] Choe et al. (1992)

; [37] Qiu et al. (1995)

; [38] Moser et al. (1997)

; [39] Parge et al. (1995)

; [40] Huang, Xue et al. (1998)

; [41] Li de la Sierra et al. (1997)

; [42] Stein et al. (1994)

; [43] Emsley et al. (1996)

; [44] Lobkovsky et al. (1993)

; [45] Schonbrunn et al. (1996)

; [46] Sixma et al. (1991)

; [47] Ozaki et al. (1991)

; [48] Stein et al. (1992)

; [49] Choudhury et al. (1999)

; [50] Sauer et al. (1999)

; [51] Cirilli et al. (1993)

; [52] Hennig et al. (1999)

; [53] Bruns et al. (1997)

; [54] Kuzin et al. (1999)

; [55] Gouet et al. (1995)

; [56] Rossjohn, Polekhina et al. (1998)

; [57] Gong et al. (1997)

; [58] Athanasiadis et al. (1994)

; [59] Isupov et al. (1998)

; [60] Baumann (1994)

; [61] Wolf et al. (1998)

; [62] Perrakis et al. (1994)

; [63] Tews et al. (1996)

; [64] Miller et al. (1994)

; [65] Arnoux et al. (1999)

; [66] Yoshimoto et al. (1999)

; [67] Murray et al. (1995)

; [68] Ling et al. (1998)

; [69] Merritt et al. (1994)

; [70] Zhang et al. (1995)

; [71] Hu et al. (1997)

; [72] Stuckey et al. (1994)

; [73] Miyatake et al. (1995)

; [74] Pearl et al. (1994)

; [75] Adman et al. (1978)

; [76] Almassy & Dickerson (1978)

; [77] Fulop et al. (1995)

; [78] Allured et al. (1986)

; [79] Gatti et al. (1994)

; [80] Beaman et al. (1998)

; [81] Kallarakal et al. (1995)

; [82] Nurizzo et al. (1997)

; [83] Villeret et al. (1995)

; [84] Frankenberg et al. (1999)

; [85] Thayer et al. (1991)

; [86] Han et al. (1995)

; [87] Hulsmeyer et al. (1998)

; [88] Toney et al. (1993)

; [89] Kim et al. (1997)

; [90] Correll et al. (1992)

; [91] Concha et al. (1996)

; [92] Mande et al. (1996)

; [93] Roe et al. (1998)

; [94] Gourley et al. (1999)

; [95] Li et al. (2000

); [96] Baca et al. (2000

); [97] Dessen et al. (1995)

; [98] Chang, Spencer et al. (1998)

; [99] Sharma et al. (1998)

; [100] Cooper et al. (1995)

; [102] Beaman et al. (1997)

; [103] Li et al. (1997)

; [104] Crennell et al. (1994

The crystal structures of many bacterial dihydrofolate reductases, the target of several antimicrobials including trimethoprim, have also been reported. Recently, the atomic structure of dihydropteroate synthase (DHPS), the target of sulfa drugs, has been elucidated, almost 60 years after the first sulfa drugs were used to treat patients (Achari et al., 1997; Hampele et al., 1997).

A very special set of bacterial proteins are the toxins. Some of these have dramatic effects, with even a single molecule able to kill a host cell. These toxins outsmart and (mis)use many of the defence systems of the host, and their structures are often most unusual and fascinating, as recently reviewed by Lacy & Stevens (1998). The structures of the toxins are actively used for the design of prophylactics and therapeutic agents to treat bacterial diseases [see e.g. Merritt et al. (1997), Kitov et al. (2000) and Fan et al. (2000)]. It is remarkable that the properties of these devastating toxins are also used, or at least considered, for the treatment of disease, such as in the engineering of diphtheria toxin to create immunotoxins for the treatment of cancer and the deployment of cholera toxin mutants as adjuvants in mucosal vaccines. Knowledge of the three-dimensional structures of these toxins assists in the design of new therapeutically useful proteins.

References

Achari, A., Somers, D. O., Champness, J. N., Bryant, P. K., Rosemond, J. & Stammers, D. K. (1997). Crystal structure of the anti-bacterial sulfonamide drug target dihydropteroate synthase. Nature Struct. Biol. 4, 490–497.Google Scholar

Cole, S. T., Brosch, R., Parkhill, J., Garnier, T., Churcher, C., Harris, D., Gordon, S. V., Eiglmeier, K., Gas, S., Barry, C. E. III, Tekaia, F., Badcock, K., Basham, D., Brown, D., Chillingworth, T., Connor, R., Davies, R., Devlin, K., Feltwell, T., Gentles, S., Hamlin, N., Holroyd, S., Hornby, T., Jagels, K., Krogh, A., McLean, J., Moule, S., Murphy, L., Oliver, K., Osborne, J., Quail, M. A., Rajandream, M. A., Rogers, J., Rutter, S., Seeger, K., Skelton, J., Squares, R., Squares, S., Sulston, J. E., Taylor, K., Whitehead, S. & Barrell, B. G. (1998). Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature (London), 393, 537–544.Google Scholar

Fan, E., Zhang, Z., Minke, W. E., Hou, Z., Verlinde, C. L. M. J. & Hol, W. G. J. (2000). A 10⁵ gain in affinity for pentavalent ligands of E. coli heat-labile enterotoxin by modular structure-based design. J. Am. Chem. Soc. 122, 2663–2664.Google Scholar

Hampele, I. C., D'Arcy, A., Dale, G. E., Kostrewa, D., Nielsen, J., Oefner, C., Page, M. G., Schonfeld, H. J., Stuber, D. & Then, R. L. (1997). Structure and function of the dihydropteroate synthase from Staphylococcus aureus. J. Mol. Biol. 268, 21–30.Google Scholar

Kitov, P. I., Sadowska, J. M., Mulvey, G., Armstrong, G. D., Ling, H., Pannu, N. S., Read, R. J. & Bundle, D. R. (2000). Shiga-like toxins are neutralized by tailored multivalent carbohydrate ligands. Nature (London), 403, 669–672.Google Scholar

Lacy, D. B. & Stevens, R. C. (1998). Unraveling the structure and modes of action of bacterial toxins. Curr. Opin. Struct. Biol. 8, 778–784.Google Scholar

Merritt, E. A., Sarfaty, S., Feil, I. K. & Hol, W. G. J. (1997). Structural foundation for the design of receptor antagonists targeting E. coli heat-labile enterotoxin. Structure, 5, 1485–1499.Google Scholar

Murray, C. J. & Salomon, J. A. (1998). Modeling the impact of global tuberculosis control strategies. Proc. Natl Acad. Sci. USA, 95, 13881–13886.Google Scholar

International Tables for Crystallography (2006). Vol. F. ch. 1.3, p. 13