Antibiotics: Modes of action, resistance mechanisms and the search for new compounds

Infectious diseases caused by microorganisms are still the prime cause of mortality despite the large number of antibacterial agents developed in the last century representing 33-40 % of death causes worldwide. Among such diseases malaria caused by plasmodia is still the number one killer. There are more than 30 new infectious diseases today that were unknown 20 years ago and some known infectious diseases re-appear with an increasing intensity. Widespread antibiotic use has resulted in a rapid spread of multi-drug resistant pathogens and it has become both a local and global health problem. Numbers of antibiotic resistant bacteria permanently increase and many pathogens have become multi-drug resistant (e.g. Mycobacterium tuberculosis). Some microorganisms that have previously been considered non-pathogenic cause serious nosocomial infections, especially in intensive care units (e.g. Acinetobacter baumanni, Pseudomonas aeruginosa, Bacteroides etc.). Particularly serious are infections caused by viruses such as HIV, Ebola, West-Nile and recently SARS and avian influenza. Of the microorganisms known today, some can be used as biological weapons. In the past, about 25 naturally occurring microorganisms (bacteria and viruses) and toxins have been considered for use as biological weapons. Among them Bacillus anthracis, Yersinia pestis, Francisella tullarensis, Brucella sp., Vibrio cholerae and viruses such as West-Nile, Ebola, Marburg, smallpox, influenza etc. have been considered as likely candidates. Several approaches are presently used to combat infectious diseases and to look for new antimicrobials and new derivatives of known compounds. They include search for new targets in pathogenic bacteria based on genome sequencing, production of new protective vaccines, the use of probiotics to increase immunological response, intensive search for new producers of biologically active compounds, production of new hybrid antibiotics, mainly against resistant bacteria, and chemical transformation and biotransformation using intact cells or isolated enzymes. Genetic and biochemical control of production of secondary metabolites including antibiotics, have certain specific features that can be used for the production of new compounds or new derivatives of known compounds