Antibiotics of the Virginiiamycin Family, Inhibitors Which Contain Synergistic Components C
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MICROMOLoGIcAL REVIEWs, June 1979, p. 145-198 Vol. 43, No. 2 0146-0749/79/02-0145/54$02.00/0 Antibiotics of the Virginiiamycin Family, Inhibitors Which Contain Synergistic Components C. COCITO Department ofMicrobiology and Genetics, Institute of Cell Pathology, University of Louvain Medical School, Brussels 1200, BeLgium INTRODUCION ............................................................. 146 CEAMEISTRY AND PHYSICS OF VIRGINIAMYCIN-LIKE ANTIBIOTICS ...... 146 Chemical Structure and Synthesis .......................................... 146 Biophysical Properties of Virginiamycin-Like Antibiotics ... 150 Chemical and Physical Determinations of Virginiamycin-Like Antibiotics ... 152 ACTION OF VIRGINIAMYCIN-LIKE ANTIBIOTICS ON BACTERIA ........ .. 152 Alterations of Growth and Viability in Bacilli ............................... 152 Macromolecule Formation in the Presence of Virginiamycins ............ ... 156 Metabolism of Polysomes and Ribosomes in Bacillus subtUis ................ 167 Mutation to Virginiamycin Resistance and Mapping of Resistance Genes .... 159 Inhibition of Cell Division in Bdellovibrio ................................... 162 TRANSIENT AND PERMANENT BLEACHING OF ALGAE BY ANTIBIOTICS OF THE VIRGINIAMYCIN FAMILY .................... 163 Cell Growth and Chlorophyll Synthesis in Eugkna .......................... 163 Chloroplast Morphogenesis and Ribosome Formation in Algae ..... .... 164 Inhibition of Growth and Macromolecule Synthesis in Cyanophyces .... 166 Action of Virginiamycin on Isolated Plant Chloroplasts .............. ... 167 MACROMOLECUILE METABOLISM IN VIRUS-INFECTED PROCARYOTES IN THE PRESENCE OF VIRGINIAMYCIN-LIKE ANTIBIOTICS ....... 167 Interference with the Multiplication of Virulent Bacteriophages ..... 167 Alteration of the Lytic Cycle of a Temperature Cyanovirus ...... ..... 169 ACTION OF VIRGINIAMYCIN-LIKE ANTIBIOTICS IN CELL-FREE SYSTEMS FROM BACTERIA AND IN SUBORGANELLAR SYSTEMS FROM EU- CARYOTES ............................ 170 Inhibition of Protein Synthesis in Cell-Free Systems from Bacteria and in Lysates of Cytoplasm Organelles .......................................... 170 Interference with Initiation and Elongation of Peptide Chains In Vitro .... 170 Binding of Type A Virginiamycins to Bacterial Ribosomes In Vitro . 173 Fixation of Type B Virginiamycins to Ribosomal Subunits and Components 175 Molecular Mechanism of Virginiamycin-Like Antibiotics .................... 177 USE OFVIRGINIAMYCIN-LIKE ANTIBIOTICSIN HUMANS AND IN ANIMALS 179 Pharmacological and Therapeutic Studies .................................. 179 Toxicological Investigation ..................... 181 Therapeutic Application of Virginiamycin-Like Antibiotics in Human Medi- cine .............................................. 183 Use of Virginiamycin-Like Antibiotics in Domestic Animals .183 Comments on the Present Applications of Virginiamycin-Like Antibiotics ... 185 SUMMARY ................................................. 186 LITERATURE CITED ....................................... 188 INTRODUCTION Numerous virginiamycin-like antibiotics have The study of synergistic effects among anti- been obtained in laboratories of different coun- biotics is an interesting development of the tries (6, 7, 18, 20,40,45, 48, 85, 100, 102, 127, 135, branch of biological sciences which deals with 151, 187, 209, 235, 247-249, 270, 298, 301, 318, inhibitors of cell growth and multiplication. 323, 328), and, in fact, most of the leading phar- Within this domain, the antibiotics of the virgi- maceutical industries have patented products of niamycin family have captivated the interest of this kind. In Table 1, the main commercial prep- scientists and physicians because of their unique arations and their sources are reported. features. The crude product obtained by the In spite of the large number of preparations producing organisms, a group of streptomycetes, available, however, virginiamycin-like antibiot- contains several components which display a ics represent a very small and homogeneous synergistic inhibitory effect in sensitive cells. group of drugs. Two basic chemical structures, 145 146 COCITO MICROBIOL. REV. TABLE 1. Commercialpreparations of virginiamycin-like antibiotics Producing orga- Antibiotic name Company nism Doricin Squibb Patricin Squibb 21 Vemamycin Squibb Etamycin Bristol Streptomyces lav- endulae Geminimycin Chas. Pfizer S. olivaceus Synergistin Chas. Pfizer S. olivaceus )27 (PA114) Mikamycin Kanegafuchi S. mitakaensis Ostreogrycin Glaxo S. ostreogriseus (E129) Plauracin Eli Lilly S. diastaticus (A2315A) Streptogramin Eli Lilly S. diastaticus Pristinamycin Rh6ne-Poulenc S. pristinaespiralis (RP7293) 27 28 Pyostacin Rh6ne-Poulenc S. pristinaespiralis 34 38 Me Me Streptogramin Merck S. graminofaciens 0 0 -26 Vernamycin Olin Mathieson S. loidensis Virginiamycin R.I.T. (Re- S. virginiae 20~~~~~~~~~~~2 (Staphylomy- cherche & Ind. 210 22 3 2 cin) Therapeu- 192IN 24 1/j0 2',j tiques) Viridogrisein Parke Davis S. griseus NRRL 17 -N18 35 37 5 2426 Griseoviridin Parke Davis S. griseoviridus 3636~~~~7/< HN "030 is 15 14 12 10 8 A and B, are shared by the components of all 1 13 1 9 known inhibitors of this family; various products differ only in minor functional groups. A 0 OH Me The aim of the present review article is to B 33 32 31 report basic data and recent findings concerning the structure and the mechanisms of action of virginiamycin-like antibiotics. Main results in the field will be summarized, and theories ex- plaining the synergistic effect of the components will be discussed. Earlier reviews on these anti- 21( biotics were made by Tanaka (282) and Vazquez (312, 315). Reference can be made also to more general articles on protein synthesis inhibitors (27, 33, 125, 161, 162, 177, 239, 241, 244, 314, 316, 331), where data on virginiamycin-like antibiot- ics are reported and discussed. 16l CHEMISTRY AND PHYSICS OF VIRGINIAMYCIN-LIKE ANTIBIOTICS OH Me C 33 32 31 Chemical Structure and Synthesis FIG. 1. Chemical structure of group A virginia- All of the antibiotics of the virginiamycin fam- mycin-like antibiotics. The configurational formulas ily can be assigned to either one of the two basic of three compounds of this group, which have been primary structures, A and B (Fig. 1 and 2; Table chemically characterized to date, are as follows: (A) 2). Although the two formulas are completely griseoviridin; (B) ostreogrycin G; (C) madumycin II. a exists in the overall Related to the former structures are those oftwo other different, yet similarity well characterized antibiotics: ostreogrycin A (A24 37 architecture of the two molecules: both of them in formula B) and madumycin I (R 1R > 0 in formula are macrocyclic lactone peptolides (10, 20, 30, C). Mikamycin A, PA114A, pristinamycin IIA, strep- 74, 127, 179, 187, 235, 288, 295, 321, 322). togramin A, vernamycin A, and virginiamycin Ml Compounds of the A group are polyunsatu- share the formula of ostreogrycin A. Pristinamycin rated cyclic peptolides, which can be considered IIB and virginiamycin M2 have the structure of os- as highly modified depsipeptides (30). The basic treogrycin G. According to references 30 and 75. VOL. 43, 1979 ANTIBIOTICS OF THE VIRGINIAMYCIN FAMILY 147 which has a mo- TABLE 2. Components of antibiotics of the structure of these compounds, family lecular weight of about 500, was mainly estab- virginiamycin lished by X-ray crystallography and mass spec- Complex anti- Type A compo- Type B compo- trometry (26, 45, 82, 83, 169) and also by identi- biotic nents nents Madumycin Madumycin II Madumycin I A OH (A2315A) Mikamycin Mikamycin A Mikamycin B Ostreogrycin Ostreogrycins A, Ostreogrycins B (E129) C, D, G, Q (Bi, B2, B3) NH R' CH2 CH2 Patricin Patricins A and B CH3-CH--CH--OO-CO-N-CH Plauracin Plauracin II Plauracin I Pristinamycin Pristinamycins H Pristinamycins I (A, NR 2 (Pyostacin) (A and B) B and C) Streptogramin Streptogramin A Streptogramin B OC-CH--W- Z )-CO-CH Synergistins Synergistin A Synergistins B (1 (PA114) and 3) CH2 Vernamycin Vernamycin A Vernamycins B (a, 1,y,O) Griseoviridin Viridogrisein (Eta- mycin) (Doricin) (C) Name(s) R' R2 R3 Z Virginiamycin Virginiamycins VirginiamycinsS (1, Patricin B C2H5 CH3 H Pipecolic acid (Staphylomy- M (1 and 2) 2, 3, and 4) Virginiamycin SI C2H5 CH3 H 4-Oxopipecolic cin) acid Virginiamycin S4 CH3 CH3 H 4-Oxopipecolic acid fication of the hydrolysis products (220-222). Virginiamycin S2 C2H5 H H 4-Hydroxypi- Four antibiotics of type A have been chemically pecolic acid characterized already: griseoviridin (Fig. 1A), Virginiamycin S3 C2H5 CH3 H 3-Hydroxy-4- oxopipecolic ostreogrycins A and G (Fig. lB), and madumycin acid II (Fig. 1C). Virginiamycin Ml, ostreogrycin A, Streptogramin B pristinamycin HA, streptogramin A, PA114A1, Mikamycin IA vernamycin A, and mikamycin A share the same 4-Oxopipecolic PA114B1 fornula (C28Hm5N307, molecular weight 525). Pristinamycin A C2H5 CH3 N(CH3)2 acid Vernamycin Ba The double bond A-2,3 is saturated in virginia- Ostreogrycin B mycin M2, ostreogrycin G, and pristinamycin Pristinamycin ICi 4-Oxopipecohic IIB. All components of the A group contain a Vemnamycin B1y CH3 CH3 N(CH3)2 acid substituted aminodecanoic acid and an unusual Ostreogrycin B1 oxazole system, presumably derived from a cy- Pristinamycin IB 4-Oxopipecohic didehydroserine residue (30). Venamycin B,/ C2H5 CH3 NHCH3 acid clized Ostreogrycin B2 Compounds of the B group are cyclic hexa- Vernamycin BS CH3 CH3 NHCH3 4-Oxopipecohc depsipeptides of molecular weight of about 800. acid The primary structure, which