Chemistry: molecular biology and microbiology – Micro-organism – per se ; compositions thereof; proces of...
Reexamination Certificate
2000-05-03
2003-06-24
Low, Christopher S. F. (Department: 1653)
Chemistry: molecular biology and microbiology
Micro-organism, per se ; compositions thereof; proces of...
C514S013800, C514S014800, C530S326000, C530S412000
Reexamination Certificate
active
06582949
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to novel peptaibol antibiotics, called cephaibols, which are synthesized from
Acremonium tubakii
FH 1685 DSM 12774 during fermentation and released into the culture medium, a process for the isolation of the cephaibols from the culture medium and their purification, and the use of the cephaibols as pharmacologically active compounds, in particular for the control of parasites.
BACKGROUND OF THE INVENTION
Parasitoses are widespread and cause a wide spectrum of pathological effects in humans and animals, which range from slight physiological disturbances to severe, even fatal disorders. Nowadays, many intensively researched parasite disorders are known which threaten the health and the life of humans, their pets, and farm animals.
Globally, the weakening of the immune system is to be increasingly found in millions of humans. This group of people is so massively affected by opportunistic parasites that, annually, millions of deaths are mourned. In the age of long-distance travel, even in non-third world countries, which normally have a high standard of hygiene, exotic parasites have to be expected. This has its origins in the fact that there is an ever increasing trend to go on trekking trips under local hygiene conditions and that—because of the supposed safety in one's own country—there is a loss of the feeling/knowledge about hygiene dangers in other countries. In addition to the protection of human health, protection of animals from the suffering and pain caused by parasitoses is required either by a cure or, if possible, by prevention. Economic reasons especially come to bear in farm animal husbandry, where, owing to unfavorable conditions for the keeping and feeding of animals (e.g., in certain forms of mass animal husbandry), parasitic disorders occur which contribute to a quantitative loss (reduction in yield of meat, number of eggs, racing pace) or a qualitative loss (quality of meat and wool). The great damage that is caused by parasitoses in humans and animals makes their control desirable, if not indispensable, in the interests of health and economy.
Parasites are unicellular or multicellular organisms which reside temporarily or permanently in (endoparasites) or on (ectoparasites) foreign organisms and live at the expense of the host. In humans and animals, many parasites lead to subacute and also to dramatic disorders. The unicellular parasites include the protozoa, such as, for example, plasmodia (malaria pathogen), trypanosomes (Chagas disease pathogen), amoebae, trichomonads or toxoplasmae. Important unicellular parasites are the endoparasitic worms (helminths), of which the threadworms (nematodes), tapeworms (cestodes) and leeches (trematodes) can cause serious damage in humans and animals. The multicellular ectoparasites include ticks, mites, lice, fleas and other organisms. Although there are a large number of agents available for the control and treatment of parasitic disorders (antiparasitics), on the one hand because of the side effects of these agents and on the other hand because of the increasing formation of resistance, there is a great need for novel, highly effective protozoicides, anthelminthics, and other parasiticides. Infestation with parasites in particular affects the population of the tropical regions; the number of those affected here is estimated at many hundreds of millions of people, in addition to the considerable damage in the agricultural field.
The use of chemical substances, whose activity against individual parasites or relatively large groups of parasites is known and which are toxicologically acceptable in the host (humans, animals) still have overriding importance in parasite control.
According to their spectrum of action, a differentiation is made between anthelminthics acting against helminths, antiprotozoals active against protozoa, insecticides active against insects, and acaricides active against mites (acaria); the last two groups are also summarized under the term ectoparasiticides.
There has been an increase in pharmaceutical resistance caused by long term and intensive use, particularly in modern mass animal husbandry. There has also been an increased occurrence of severe side effects to present medications, in particular of continuous medication of people who, within the framework of progressive globalization, have to work for a relatively long time in the tropics and subtropics. These factors combined with the high cost of prophylaxis/therapy with certain chemotherapeutics makes the search for inexpensive classes of substances having a different mechanism of action and better tolerability essential. Antiparasitics are also needed which are not only effective, but also economically preparable in large amounts, and moreover, environmentally friendly.
Bacteria and fungi via their secondary metabolism by means of nonribosomal peptide synthetases produce peptides having up to 20 amino acids, and in some cases structurally unusual amino acids. Many of the previously known secondary metabolites having a peptide structure possess interesting biological actions as antibiotics, enzyme inhibitors, cardiotonics, immunomodulators, insecticides, nematocides and many others (see, for example, Gräfe,
U. Biochemie der Antibiotika
, Spektrum Heidelberg, 1992).
Within the structural class of peptide active compounds, the so-called peptaibols are distinguished in that they unusually contain many amino acids (up to 20, among them a high proportion of &agr;-aminobutyric acid (Brückner, H., König, W. A., Greiner, M., Jung, G. Angew.
Chem. Int. Ed. Engl
. 18:476-477(1979)). In addition, peptaibols are very often acetylated at the N terminus and contain a radical having an alcohol group (e.g., phenylalaninol) or an aldehyde group at the C terminus.
Examples of peptaibols, as addressed above, are aibellin [
J. Antibiotics
47:1136-1144 (1994)]; ampullosporin [
J. Antibiotics
50:72-728, (1997)]; antiamoebin [
Structure
6:783-792 (1998)]; clonostachin [
J. Antibiotics
50:105-110 (1997)]; emerimicins [
J. Antibiotics
, 27:274-282 (1974)] or zervamicins [
J. Antibiotics
, 27:321-328 (1974)]. These peptaibols are synthesized by very different strains of the genera Emericellopsis, Trichoderma, Apiocrea, and many others. They display their antibiotic activity against gram-positive bacteria, against some types of fungi, and against amoebae. The antipyretic and neuroleptic action of ampullosporin has moreover been described.
The previously known peptide active compounds, however, often have disadvantages that are manifested in unsatisfactory potency of action, high toxicity, and/or undesired side effects.
SUMMARY OF THE INVENTION
The object of the invention is therefore to search for novel microbial peptide active compounds having improved properties and/or novel mechanisms of action.
This object is achieved, according to the invention, by fermenting the strain
Acremonium tubakii
FH 1685 DSM 12774 in a nutrient solution having a carbon and nitrogen source, as well as the customary inorganic salts, until the novel peptaibols, called cephaibols, accumulate in the culture medium, then isolating the cephaibols from the culture medium, and optionally, separating the cephaibols into the individual active peptide compounds. The isolated cephaibols are pharmacologically active and are, thus, suitable for use as pharmaceuticals. Because of their antiparasitic properties, in particular their strong anthelmintic activity and insecticidal action on ectoparasites, they can be employed, in particular, as antibiotics having action against endo- and ectoparasites in animals and in humans.
The invention thus relates to
1. A compound of the formula I (SEQ ID NO:9)
AcPhe-Aib-Aib-Aib-x-w-Leu-y-Aib-Hyp-Gln-z-Hyp-Aib-Pro-R (I)
wherein R is Phe-ol or Phe-al and w, x, y, and z have the following meanings:
a) w is Gly or Ala; x is Aib and y and z are Iva;
b) w is Gly; x, y and z are Iva;
c) w is Gly; x and z are Aib and y is Iva;
d) w is Gly; x, y and
Hofmann Joachim
Kurz Michael
Schiell Matthias
Vértesy László
Aventis Pharma Deutschland GmbH
Kam Chih-Min
Low Christopher S. F.
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