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Screening of New Antibiotics

#1848


Screening, Identification and Study of Specific Activity and Toxical Properties of New Antibiotics, Active Against Multidrug Resistant Microbial Agents of Nosocomial Infections

Tech Area / Field

  • BIO-MIB/Microbiology/Biotechnology
  • MED-DRG/Drug Discovery/Medicine

Status
8 Project completed

Registration date
12.04.2000

Completion date
12.08.2005

Senior Project Manager
Weaver L M

Leading Institute
Gause Institute of New Antibiotics, Russia, Moscow

Supporting institutes

  • Research Center of Toxicology and Hygienic Regulation of Biopreparations, Russia, Moscow reg., Serpukhov

Collaborators

  • Mukogava Women's University, Japan, Nishinomiya\nVanderbilt University, USA, TN, Nashville

Project summary

The aim of the project is development of new, promising for practical medicine, wide spectrum antibiotics on the basis of actinomycetes screening, chemical isolation and structure study, as well as microbiological, toxicological, and pharmacological investigations.

The given project deals with one of the most topical problems of microbiology, bioorganic chemistry and medicine, namely, creating effective antibiotics of bacterial origin, which suppress pathogenic microflora, including resistant to wide applied antibiotics and chemotherapeutic drugs.

The second half of the 20th century is the era of antibiotics, which take the leading part in modern chemotherapy of bacterial infections and oncological diseases. The use of antibiotics in medicine promoted successful control over severe infections, and, on the whole, progress in medicine, demography “explosions” and human life prolongation.

However, for the period of antibiotics using in clinical practice, steady growth of clinically significant bacteria tolerance to these preparations has been observed. This is likely to be an unavoidable process. Selection of resistant to antibiotics mutants is especially rapid in populations of opportunic pathogenic microorganisms, which, in turn, often act as donors of resistance genes for particularly dangerous infections agents. Recently, the number of diseases, caused by multidrug resistant gram-positive microorganisms, has been continuously increasing. First of all, this concerns staphylococci, especially populations of meticillino-resistant staphylococci, characterized by resistance to the basic groups of contemporary antibiotics (betalactam, tetracycline, aminoglycoside, macrolides), and having increasing heterogenicity of susceptibility to phusidin and rifampicin.

Meticillino-resistant staphylococci are frequent agents for the most severe forms of nasocomial infections (angiogene sepsis, endocarditis following cardiological operations, generalised wound infection, etc.) especially in facilities for reanimation, intensive therapy, cardiosurgery and others.

Enterococci are the second group of microorganisms, whose frequency as severe infection agents in hospitals (urosepsis, angiogene sepsis, endocarditis and others) has sharply increased. This is connected with natural resistance of enterococci to most groups of antibiotics, especially to cephalosporins, whose selective pressure on normal microflora during the process of intensive antibioticotheraphy has led to spreading and turning Enterococcus faecalis and Entericoccus faecalis into agents of severe infective inflammatory diseases. So, prevalence of pathogenous bacterial strains, resistant and multiresistant to various antibacterial formulations, including up-to-date penicillins, cephalosporins and glycopeptides of Vancomycin group, requires development of new theoretical and experimental approach to overcome their resistance.

The optimal way to settle the problem of resistance is the way of search among secondary metabolites of bacterial origin for highly active, low toxic natural compounds, blocking, in contrast to widely used antibiotics, new cellular “targets” of bacteria.

To date, more than 20,000 secondary metabolites of bacterial origin, possessing various biological activity, are known. Their screening and study of interrelation between the structure and biological activity are conducted in many laboratories all over the world – in Japan, USA, Great Britain, Italy, etc.[10, 25, 33]. The mechanism of action is established, and targets and structural elements of molecule, responsible for displaying biological activity, are determined for some secondary metabolites.

It is known that the most promising group of microorganisms, capable of forming antibiotics, is actinomycetes. More than 60 per cent of all known antibiotics and more than 90 per cent of antibiotics, that have found application for chemotherapy, have been isolated from them. Most of antibiotic producers belong to Streptomyces genus. Preliminary study, conducted by the authors, and reference data demonstrate that soil actinomycetes are an inexhaustible source of biologically active substances having different impact spectrum and various chemical structure. Such important antibiotics as ristomycin-A, heliomycin, eremomycin, rubomycin, tobramycin, monomycin, оlivomycin, etc. have been produced from actinomycetes in the Research Institute of New Antibiotics at the Russian Academy of Medical Sciences.

The given project aims at creating new antibacterial preparations, active for resistant and multidrug resistant strains of pathogenous microflora, by the methods of microbiology and bioorganic chemistry.

To attain the goal it is necessary:

- To isolate natural strains of actinomycetes, to conduct primary screening of potential antibiotics, and to study antibiotics spectrum in standard microbial test-organisms;

- To determine and study antibacterial and toxical properties of antibiotic concentrates from promising strains-producers including concerning agents of nasocomial infections with multiplex antibioticoresistance;

- To isolate from stock culture, to purify, and to study physical and chemical properties and identify antibiotics, selected of strains-producers;

- To assess parameters of antibiotics toxicity for warm-blooded animals, their antibacterial properties in vitro and in vivo in models of nasocomial infections agents with multiplex antibioticoresistance;

- To study taxonomy of initial strains-producers, their pathogenicity for warm-blooded animals, to draw up R&D documentation for promising strains patenting.

- To prepare recommendations for new drugs development, to draw up R&D documentation for promising antibiotics patenting.

The results of the work will be the basis for systematic investigations of structural and functional properties of new antibiotics and their chemical modification. It will make possible creating antibiotics of new generation, possessing higher specific antibacterial activity, selective effect and less toxicity.

Scientific novelty of the planned investigations will be in discovering new producers of biologically active substances, new types of biomolecules’ chemical structure, as well as new drugs for medical purposes. The results obtained during the project implementation can be used further to create algorithmic systems of antibacterial therapy for severe infections. Isolated during the work new antibiotics formulations and corresponding strains-producers will be of global novelty and may be the objects for patenting.

The importance of the problem is confirmed by necessity to develop drugs, active for problem multidrug resistant microorganisms-infectious diseases agents. Such formulations are vitally necessary for large contingent of patients, as infectious diseases, caused by resistant forms of bacteria, take the leading part in humans’ pathology. A real basis to attain the goal is long-standing experience of project participants in the field of new antibiotics screening, their isolation, purification, biochemical analysis and also toxicological assessment of microorganisms, as well as preclinical trials of specific activity and possible side effect of new drugs, putting into medical practice.

The project is of great economic and social significance, and it is expected to contribute considerably in the most immediate problem of medicine – control over infectious diseases, caused by multidrug resistant microorganisms. This would improve infections prophylaxis and patients treatment, reduce out-patient and hospital treatment terms, bring down human disablement and, as a result, mortality in Russia and all over the world.

The project implementation will contribute in one of the most important social problems on reorientation of scientific interests and using scientific and creative potential of scientists and engineers, previously employed for Defense industry, to fundamental and applied investigations in biology, biochemistry, oncology, and medicine for peaceful purposes, in the International scientific society’s framework.

According to the results of the investigations:

- New strains-producers of antibiotics, active for multidrug resistant microorganisms and promising for use in medicine and veterinary medicine, will be selected.

- A new wide spectrum antibiotic will be found, its physic-chemical, specific biological and toxicological properties as well as field of application will be analyzed; the technology for producing, having commercial significance, will be elaborated.


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