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Selective toxicity, side effects and resistance
International Journal of Antimicrobial Agents 14 (2000) 171 www.ischemo.org
Special issue—Non Antibiotics
1. Introduction
1.1. Selecti6e toxicity, side effects and resistance Selective toxicity has been the main objective of the search for new drugs ever since the advent of chemotherapy. Man and microbe are so different that there must be some special targets in microbes that are not found in man, that should be the focus of attack by agents that will destroy the microbe and leave man intact. The cell wall of bacteria is an obvious difference to the fragile cells of man. This difference has been well exploited by beta-lactam drugs of great variety from 1940 onwards. And as for the thymidylate, man uses preformed folate whereas bacteria have to synthesise it. Each biological phenomenon displayed by antibiotics and microbes has been explained away when the mode of action has been dissected down to the molecular level. So why after 100 years of chemotherapy do we still have side effects? Selective toxicity has been a holy grail difficult to unearth. The trouble is that man and microbe are too much alike. With our status as the highest form of life, it has been easy to visualise the relentless progression of evolution from archeabacteria via prokaryote to eukaryote and onto the fragile cells of Homo sapiens. Unfortunately, when all these life forms were in the melting pot, considerable sharing of DNA between pro- and eukaryotes went on and still continues today. Nucleic acids and the life energy source are common to us all. The classification of life forms via 16S ribosomal nucleic acid (RNA) has demonstrated that we have more in common with microbes than we might wish. Proteins are the usual target of drugs. Antibiotics are chemicals just as are neuroleptics. Why therefore should drugs be classified into antibiotics and non-antibiotics?
A large body of literature now illustrates phenomena which I call concordant pharmacodynamics of man and microbe — starting from the use of methylene blue in the 1980s, not only as a tranquilliser but also for treating malaria, to the use of sulphonamides as antibiotic drugs and as diuretics and insulin stimulators in the 1950s, to the use of macrolides as motolins and immunomodulators today. In the 1990s, there has been an impressive collection of evidence to show drugs are drugs and similar molecular structures affect man and microbe although perhaps in different ways. Resistance to antimicrobials has been noted since the first uses of such compounds to treat parasite infections. Since antibacterials appeared, the galaxy of new resistance mechanisms has provided much intellectual stimulation over 60 years. In some instances, unfortunately, the resistances are beginning to overtake the range of antibiotics available. Resistance to drugs other than to antibacterials, antivirals, antifungals and antiparasitic agents may not impinge much on the infection practitioners and scientist. However, cancers become resistant to anti-cancer drugs, mammalian targets become acclimatised or tolerant to many pharmaceuticals. The major obsession of microbiologists with resistance is shared by all practitioners. The papers collected in this special issue of the Journal are those which touch some of the problems described in this introduction. Can non-antibiotics be used to treat infection, to overcome or even to reverse resistance, to be adjuvants to antibiotics, to modify the host response? Of course the answer to all these is yes.
.
0924-8579/00/$ 20 © 2000 Elsevier Science B.V. and International Society of Chemotherapy All rights reserved. PII: S 0 9 2 4 - 8 5 7 9 ( 0 0 ) 0 0 1 5 4 - 0
J.D. Williams London, UK
Special issue—Non Antibiotics
1. Introduction
1.1. Selecti6e toxicity, side effects and resistance Selective toxicity has been the main objective of the search for new drugs ever since the advent of chemotherapy. Man and microbe are so different that there must be some special targets in microbes that are not found in man, that should be the focus of attack by agents that will destroy the microbe and leave man intact. The cell wall of bacteria is an obvious difference to the fragile cells of man. This difference has been well exploited by beta-lactam drugs of great variety from 1940 onwards. And as for the thymidylate, man uses preformed folate whereas bacteria have to synthesise it. Each biological phenomenon displayed by antibiotics and microbes has been explained away when the mode of action has been dissected down to the molecular level. So why after 100 years of chemotherapy do we still have side effects? Selective toxicity has been a holy grail difficult to unearth. The trouble is that man and microbe are too much alike. With our status as the highest form of life, it has been easy to visualise the relentless progression of evolution from archeabacteria via prokaryote to eukaryote and onto the fragile cells of Homo sapiens. Unfortunately, when all these life forms were in the melting pot, considerable sharing of DNA between pro- and eukaryotes went on and still continues today. Nucleic acids and the life energy source are common to us all. The classification of life forms via 16S ribosomal nucleic acid (RNA) has demonstrated that we have more in common with microbes than we might wish. Proteins are the usual target of drugs. Antibiotics are chemicals just as are neuroleptics. Why therefore should drugs be classified into antibiotics and non-antibiotics?
A large body of literature now illustrates phenomena which I call concordant pharmacodynamics of man and microbe — starting from the use of methylene blue in the 1980s, not only as a tranquilliser but also for treating malaria, to the use of sulphonamides as antibiotic drugs and as diuretics and insulin stimulators in the 1950s, to the use of macrolides as motolins and immunomodulators today. In the 1990s, there has been an impressive collection of evidence to show drugs are drugs and similar molecular structures affect man and microbe although perhaps in different ways. Resistance to antimicrobials has been noted since the first uses of such compounds to treat parasite infections. Since antibacterials appeared, the galaxy of new resistance mechanisms has provided much intellectual stimulation over 60 years. In some instances, unfortunately, the resistances are beginning to overtake the range of antibiotics available. Resistance to drugs other than to antibacterials, antivirals, antifungals and antiparasitic agents may not impinge much on the infection practitioners and scientist. However, cancers become resistant to anti-cancer drugs, mammalian targets become acclimatised or tolerant to many pharmaceuticals. The major obsession of microbiologists with resistance is shared by all practitioners. The papers collected in this special issue of the Journal are those which touch some of the problems described in this introduction. Can non-antibiotics be used to treat infection, to overcome or even to reverse resistance, to be adjuvants to antibiotics, to modify the host response? Of course the answer to all these is yes.
.
0924-8579/00/$ 20 © 2000 Elsevier Science B.V. and International Society of Chemotherapy All rights reserved. PII: S 0 9 2 4 - 8 5 7 9 ( 0 0 ) 0 0 1 5 4 - 0
J.D. Williams London, UK