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

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

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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