Current Drug Targets - Infectious Disorders, Volume 2,
No. 2, 2002
Structural Based Drug Design in Antibacterial Disorders
Antibacterial Drug Discovery in the
Post-Genomics Era Pp.109-119
Claude
G. Lerner and Bruce A. Beutel
The TB Structural Genomics Consortium:
Providing a Structural Foundation for Drug Discovery Pp.121-141
Celia
W. Goulding, Marcin Apostol, Daniel H. Anderson,Harindarpal
S. Gill, Clare V. Smith, Mack R. Kuo,Jin Kuk Yang, Geoffrey S. Waldo, Se Won Suh,Radha
Chauhan, Avinash Kale, Nandita Bachhawat,Shekhar C. Mande, Jodie M. Johnston, J. Shaun Lott,Edward
N. Baker, Vickery L. Arcus, David Leys, Kirsty J. McLean, Andrew W. Munro, Joel Berendzen,Vivek
Sharma, Min S. Park, David Eisenberg,James Sacchettini, Tom Alber, Bernhard Rupp,William Jacobs, Jr. and Thomas C. Terwilliger
Aminoglycoside Antibiotic Resistance by Enzymatic
Deactivation Pp.143-160
Clyde
A. Smith and Edward N. Baker
Combating Infectious Diseases through
Multivalent Design
Pp.161-167
Erkang Fan and Ethan A. Merritt
Antibiotics Targeting Ribosomes:
Crystallographic Studies Pp.169-186
Tamar
Auerbach, Anat Bashan, Joerg Harms, Frank Schluenzen,Raz Zarivach, Heike
Bartels, Ilana Agmon,
Maggie Kessler,Marta Pioletti,
François Franceschi and Ada
Yonath
[Back to top] Antibacterial Drug Discovery in the
Post-Genomics Era
Claude G. Lerner and Bruce A. Beutel
Antibacterial
research has evolved dramatically over the past five decades. Early work relied
on serendipity of finding drug-like molecules, usually natural products that
had desirable antibacterial and nontoxic properties without regard to mechanism
of action. In the past decade, however, significant technological advances in
the fields of genomics, molecular biology, high-throughput screening, and
structural biochemistry have led to a fundamentally new paradigm in the pursuit
of novel antibacterial agents. The new methods promise to lead to the discovery
of novel drug-target pairs that will be useful in the continuing battle against
drug-resistant bacterial infections. This review describes this new paradigm,
the technologies on which it is based, and the current status of this approach
in drug discovery.
[Back to top] The TB Structural Genomics Consortium:
Providing a Structural Foundation for Drug Discovery
Celia
W. Goulding, Marcin Apostol, Daniel H. Anderson,Harindarpal
S. Gill, Clare V. Smith, Mack R. Kuo,Jin Kuk Yang, Geoffrey S. Waldo, Se Won Suh,Radha
Chauhan, Avinash Kale, Nandita Bachhawat,Shekhar C. Mande, Jodie M. Johnston, J. Shaun Lott,Edward
N. Baker, Vickery L. Arcus, David Leys, Kirsty J. McLean, Andrew W. Munro, Joel Berendzen,Vivek
Sharma, Min S. Park, David Eisenberg,James Sacchettini, Tom Alber, Bernhard
Rupp William Jacobs, Jr. and Thomas C. Terwilliger
Structural
genomics, the large-scale determination of protein structures, promises to
provide a broad structural foundation for drug discovery. The tuberculosis (TB)
Structural Genomics Consortium is devoted to encouraging, coordinating, and
facilitating the determination of structures of proteins from Mycobacterium
tuberculosis and hopes to determine 400 TB protein structures over 5 years. The
Consortium has determined structures of 28 proteins from TB to date. These protein
structures are already providing a basis for drug discovery efforts.
[Back to top] Aminoglycoside Antibiotic Resistance by Enzymatic
Deactivation
Clyde
A. Smith and Edward N. Baker
Acquired resistance
to the aminoglycoside family of antibiotics has
rendered this large and important family of compounds virtually unusable.
Resistance is primarily mediated by three classes of enzymes, typically
residing on transposable elements in resistant bacteria. These enzymes, the phosphotransferases, acetyltransferases
and adenyltransferases, chemically modify the aminoglycosides, which either interferes with drug
transport or the binding of the drug at the site of antibacterial action, the
30S ribosomal subunit. The structures of several members of the aminoglycoside-modifying enzyme family are now known, and
it is hoped that through a better understanding of these enzymes, both from a
structural and mechanistic view-point, could lead to the development of either
rationally-designed novel aminoglycosides, or
specific structure-based enzyme inhibitors. Such developments could help to
bring these compounds back to the forefront of modern antimicrobial
chemotherapy. This review focuses on the structural details of the enzymes
whose crystal structures are known and on the implications of these findings
for devising novel strategies to overcome resistance to this broad class of
antibiotics.
[Back to top] Combating Infectious Diseases through
Multivalent Design
Erkang Fan and Ethan
A. Merritt
Many biological
interactions are multivalent, linking two particles via many copies of the same
ligand-receptor binding pair. Examples of multivalent
binding range from cell-cell adhesion to the assembly of large protein
complexes from constituent multimers to the binding
of AB5 bacterial toxins at the cell surface. Multivalent interactions can be
effectively mimicked, inhibited, or disrupted through the design of suitable
multivalent ligands. We review here recent work on
multivalent ligand design based on a number of
different chemical scaffolds, with a specific emphasis on the use of
structure-based ligand design to target multimeric bacterial toxins.
[Back to top] Antibiotics Targeting Ribosomes:
Crystallographic Studies
Tamar Auerbach, Anat Bashan, Joerg
Harms, Frank Schluenzen,Raz Zarivach,
Heike Bartels, Ilana Agmon,
Maggie Kessler,Marta Pioletti,
François Franceschi and Ada
Yonath
Resistance to antibiotics
is a major problem in modern therapeutics. Ribosomes,
the cellular organelle catalyzing the translation of the genetic code into
proteins, are targets for several clinically relevant antibiotics. The ribosomes from eubacteria are
excellent pathogen models. High resolution structures of the large and small
ribosomal subunits were used as references that allowed unambiguous
localization of almost a dozen antibiotic drugs, most of which are clinically
relevant.
Analyses of these
structures showed a great diversity in the antibiotics’ modes of action, such
as interference with substrate binding, hindrance of the mobility required for
the biosynthetic process and the blockage of tunnel which provides the path of
exit for nascent proteins. All antibiotics studied by us were found to bind
primarily to ribosomal RNA and, except for one allosteric
effect, their binding did not cause major conformational changes.
Antibiotics of the
small ribosomal subunit may hinder tRNA binding,
decoding, translocation, and the initiation of the entire biosynthetic process.
The large subunit agents may target the GTPase
center, interfere with peptide bond formation, or block the entrance of the
nascent protein exit tunnel. The overall structure of the peptidyl
transferase center and the modes of action of the
antibiotic agents indicate that the ribosome serves as a template for proper
positioning of tRNAs, rather than participating
actively in the catalytic events associated with the creation of peptide bonds.