Structure and Function of “Metalloantibiotics”
Medicinal Research Review 2003,
23, 697–762.
Li-June Ming
Department of Chemistry and
Institute for Biomolecular Science
University of South Florida
Tampa, Florida 33620-5250
Synopsis
Although most antibiotics do not need metal ions for their biological activities,
there are a number of antibiotics that require metal ions to function properly,
such as bleomycin, streptonigrin, and bacitracin. The coordinated metal
ions in these antibiotics play an important role in maintaining proper structure
and/or function of these antibiotics. Removal of the metal ions from
these antibiotics can cause changes in structure and/or function of these
antibiotics. Similar to the case of “metalloproteins”, these antibiotics
are dubbed “metalloantibiotics” which are the title subjects of this review.
Metalloantibiotics can interact with several different kinds of biomolecules,
including DNA, RNA, proteins, receptors, and lipids, rendering their unique
and specific bioactivities. In addition to the microbial-originated
metalloantibiotics, many metalloantibiotic derivatives and metal complexes
of synthetic ligands also show antibacterial, antiviral, and anti-neoplastic
activities which are also briefly discussed to provide a broad sense of the
term “metalloantibiotics”.
Table of contents
I. Introduction
II. DNA-Binding Metalloantibiotics
A. Bleomycin
DNA/RNA binding and cleavage
Metal binding and coordination chemistry
Zn2+ and Co2+/3+ complexes and
their DNA binding
Paramagnetic Fe2+/3+ and Co2+ complexes
Synthetic analogues
B. Aureolic Acids
Structure of aureolic acids
Role of metal ions in the action of aureolic acids
The role of sugars
NMR structure of (aureolic acid)2-Mg2+
-(DNA)2 terminal complexes
NMR structure of the paramagnetic (aureolic acid)2
-Co2+-(DNA)2 terminal complexes
C. Streptonigrin (SN)
Action of metallo-SN
Metal complexes of SN
D. Anthracyclines (AC)
Action of AC and metal-AC complexes
Fe-AC complexes
Lanthanide-AC complexes
Interactions of ACs and their metal complexes with other
biomolecules
E. Aminoglycosides
RNA-binding and aminoglycoside action
Metal binding and bioactivity
F. Quinolones
Metal complexes of quinolones
Mechanism of quinolone action
G. Cisplatin
Cisplatin-DNA complexes
Cisplatin conjugates
Cisplatin analogues
H. Organometallics
III. Metal-Tetracycline Complexes and Bacterial Resistance
Metal binding
RNA binding
Metal-dependent bacterial resistance
IV. Bacitracin and Cell Wall Biosynthesis
Metal complexes and antibiotic mechanism
Coordination chemistry of metal complexes
Structure-function relationship
V. Ionophores and Siderophores
A. Structure and cation binding and transport of ionophores
Structure and metal binding
Carboxylic ionophores
Gramicidin family
B. Iron sequestering and antibiotic activities
Structure and mechanism of siderophores
Albomycin structure and receptor binding
VI. Perspectives of Metal Ions in Medicine
Acknowledgments
References
Biosketch
I. Introduction
Antibiotics can interact with a variety of biomolecules,
which may result in inhibition of the biochemical or biophysical processes
associated with the biomolecules. This can be illustrated in the interaction
of the peptide antibiotic polymyxin with glycolipids which affects membrane
function, in the intercalation of the anthracyclines into DNA base pairs
which stops gene replication, in the imbedding of the lipophilic antibiotic
gramicidin and the insertion of the amphiphilic antibiotic protein
colicin A into cell membrane which disturb normal ion transport and
trans-membrane potential of cells, in the inhibition of transpeptidase by
penicillin which affects cell wall synthesis, and the inhibition of
aminopeptidase by bestatin, amastatin, and puromycin which impairs many significant
biochemical processes. While most antibiotics do not need metal
ions for their biological activities, there are several families of antibiotics
that require metal ions to function properly. In some cases, metal
ions are bound tightly and are integral parts of the structure and function
of the antibiotics. Removal of the metal ions thus results in deactivation
and/or change in structure of these antibiotics, such as bacitracin, bleomycin,
streptonigrin, and albomycin. In other cases, the binding of metal
ions to the antibiotic molecules may engender profound chemical and biochemical
consequence which may not significantly affect the structure of the drugs,
such as tetracyclines, anthracyclines, aureolic acids, and quinolones.
Similar to the case of “metalloproteins”, these families of antibiotics are
thus dubbed “metalloantibiotics” in our studies and are the title subjects
of this review.
The term “antibiotic” was originally coined by Selman A. Waksman and was
used in the title of a book of his, Microbial Antagonisms and Antibiotic
Substances published in 1945, and was defined as “…produced by microorganisms
and which possess the property of inhibiting the growth and even of destroying
other microorganisms ”. However, many clinically useful “antibiotic
drugs” nowadays are either synthetic or semi-synthetic, including many -lactams,
(fluoro)quinolones, and aminoglycosides. These (semi-)synthetic drugs
and many synthetic metal complexes and organometallic compounds that exhibit
“antibiotic activities” can be considered “synthetic antibiotics” as the counterparts
of the originally defined “microbial-originated antibiotics” from a broad
sense of the term. In this review, we focus on those nature-occurring
metalloantibiotics and also briefly discuss a few synthetic metalloantibiotics
to provide a broader view of the term “metalloantibiotics”. The structures
and anti-microbial, anti-viral, and/or anti-cancer activities of these natural
and synthetic metalloantibiotics will be discussed to provide further insight
into their structure-function relationship.
Metal ions play a key role in the actions of synthetic
and natural metalloantibiotics, and are involved in specific interactions
of these antibiotics with proteins, membranes, nucleic acids, and other biomolecules.
For example, the binding of Fe/Co-bleomycin, Fe/Cu-streptonigrin, Mg-quinolone,
Mg-quinobenzoxazine, Mg-aureolic acid, and cisplatin with DNA impairs DNA
function or results in DNA cleavage (Section II); the involvement of Mg/Fe
in the binding of tetracyclines to the regulatory TetR protein turns on the
mechanism for bacterial resistance to tetracyclines (Section III); the binding
of metallobacitracin to undecaisoprenyl pyrophosphate prohibits the recycling
of the pyrophosphate to phosphate which in turn inhibits cell wall synthesis
(Section IV); and the binding of metal ions to ionophores or siderophores
allows their transport through cell membrane which can cause disruption of
the potential across the membrane, enables microorganisms to acquire essential
iron from the environment, or delivers antibiotics to foreign microorganisms
(Section V). The structural and functional roles of metal ions in metalloantibiotics
have been further advanced in recent years from extensive biological, biochemical,
and physical studies, which are discussed herein to provide an overview
of this important and unique group of antibiotics.
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