Antibiotics (also known as antimicrobials) are chemical compounds used to kill or inhibit the growth of infectious organisms. Originally the term antibiotic referred only to organic compounds, produced by bacteria or molds, that are toxic to other microorganisms. Currently, the term now includes synthetics and semi-synthetic organic compounds.
Antibiotics generally refer to anti-bacterials, however, a loose definition may include such specific compounds as antivirals, anti-protozoals, and antifungal agents. All antibiotics share the property of selective toxicity, however, in that they are more toxic to an invading organism than they are to an animal or human host.
Antibiotics may be classified as bactericidal (bacterial-killing) or bacteriostatic (inhibiting bacterial proliferation). Bacteriostatic drugs are effective because bacteria prevented from multiplying will eventually be killed by the defense mechanisms of the host.
Antibiotics are further defined according to their mechanisms of action. For example, many antibiotics act by selectively interfering with the synthesis of bacterial constituents, such as the cell wall or bacterial nucleic acids. Beta-lactam antibiotics, which include the penicillins, interfere with the synthesis of peptidoglycan, the major component of bacteria cell walls. By interfering with peptidoglycan synthesis, material accumulates inside bacterial cells, exerting increasing pressure on the membrane. Eventually, the membrane ruptures and the cellular contents leak out, resulting in the bacterial death. Since mammalian cells do not have peptidoglycan, they are not affected by the action of penicillin-like agents.
Other antibiotics operate by inhibiting the synthesis of various intracellular bacterial molecules, including DNA, RNA, ribosomes, and protein. For example, antibiotics like Rifampicin inhibit enzymes involved with nucleic acid synthesis, such as DNA polymerase. By contrast, Quinoline antibiotics inhibit synthesis of the enzyme responsible for the coiling and uncoiling of the chromosomes, a process necessary for DNA replication and messenger RNA transcription. Still other pharmacologically-active compounds, such as the tetracyclines, compete with incoming transfer-RNA molecules.
One of the most common methods of classifying bacteria is based upon differential staining characteristics, using a procedure such as the Gram's stain. Some species of bacteria have a cell wall consisting primarily of a thick layer of peptidoglycan. Other species have a much thinner layer of peptidoglycan and an outer, as well as an inner, membrane. When bacteria are subjected to a Gram's stain, the differences in cell wall structure produce differential staining of the bacteria. Bacteria classified as Gram-positive organisms appear purple, while those classified as Gram-negative appear reddish.
Antibacterial drugs can also be classified according to those which are effective against Gram-positive bacteria; those with activity against Gram-negative bacteria; and those agents effective against members of both Gram-positive and Gram-negative classifications. For example, the penicillins are classified as narrow-spectrum antibiotics, with activity against many Gram-positive bacteria. The tetracyclines and chloramphenicols are classified as broad spectrum drugs because they are effective against both Gram-positive and Gram-negative bacteria.
Originally, antibiotics were primarily isolated from bacteria or from molds. Penicillin, for example, was derived from the mold Penicillium chrysogenum. The effectiveness of Penicillin as an antibiotic was accidentally discovered in 1928 by Sir Alexander Fleming, who showed its efficacy in laboratory cultures against many disease-producing bacteria. Fleming's discovery marked the beginning of the development of antibacterial compounds produced by living organisms.
Other antibiotics have been isolated from a group of soil bacteria, called actinomycetes. One of these, streptomycin, was discovered in 1944 by Selman Waksman and his colleagues. Streptomycin was originally the primary chemotherapeutic agent used against tuberculosis. The management of infectious diseases has been transformed by the use of antibiotics. The incidence of many diseases once responsible for high mortality and morbidity, such as tuberculosis, pneumonia, and bacterial meningitis, has been reduced because of successful antibiotic treatment. Indeed, a whole branch of pharmacology has been devoted to the discovery and development of synthetic antibiotics, which exhibit increased efficacy and safety for the treatment of infectious organisms.
However, the increased use of antibiotic therapy has been accompanied with a corresponding increase in the evolution of bacterial defenses against the drugs. One of the main defense mechanisms used by bacteria is the inactivation of the antibiotic molecule. This mechanism is one of the bases of bacterial resistance against both penicillin and chloramphenicol, among others.
Another bacterial defense involves a mutation which changes a bacterial enzyme, such that the antibiotic no longer effectively inhibits the bacterial growth. This is the main mechanism of resistance to compounds that inhibit protein synthesis, such as the tetracyclines.
Of even greater concern is that many mechanisms resulting in antibiotic resistance are transmitted genetically from the bacterium to its progeny. Genes that carry resistance can also be transmitted from one bacterium to another by means of plasmids (extrachromosomal pieces of DNA). Because plasmids are easily acquired and lost by bacteria, drug resistance may spread rapidly among bacterial species.
Plasmids have also been identified which carry resistance to several different classes of antibiotics, thus creating bacteria resistant to all attempts at drug therapy. For example, a strain of bubonic plague has been found recently which is resistant to multiple antibiotics.
The danger inherent in emerging drug resistance is exemplified in the disease tuberculosis In the 1970's, tuberculosis appeared to have been nearly eradicated in the United States and other developed countries. Now, its incidence is increasing at an alarming rate, partly due to the emergence of an antibiotic resistant strain.
Currently, antibiotic resistance in bacteria has reached a crisis point in healthcare, with the discovery of many bacterial isolates which display multi-drug resistance to many of the known antimicrobials. A study jointly supported by the State University of New York (Buffalo) and the University of Iowa College of Medicine analyzed over 17,000 bacterial isolates associated with hospital-acquired (nosocomial) infections, obtained from 215 medical sites across the country. Results of this study showed a sharp increase in the occurrence of antibiotic resistance among bacterial isolates.
Recent studies have shown an increase in Methicillin resistant strains of Staphylococcus aureus (MRSA), which can cause boils, pneumonia, and toxic shock. Currently, approximately 30% of the S. aureus strains isolated exhibit drug resistance. Further, in May of 1997, the Centers for Disease Control and Prevention (CDC) reported isolation of an S. aureus strain which had developed resistance to Vancomycin, one of the most powerful antibiotics currently available. Because S. aureus is the most frequent cause of nosocomial infections, this discovery alarmed healthcare workers and infectious disease specialists.
The list of resistant organisms is increasing daily. Between 1988 and 1996, researchers observed an approximately 50-fold increase in the number of Vancomycin-resistant Enterococcus strains isolated from clinical samples. Enterococcus, which can cause meningitis, heart inflammation, and stomach infections, most often affects the elderly and those with a weakened immune system. Thus, the acquistion of Vancomycin-resistance greatly concerns public health officials, as they seek to develop methods to control a potentially fatal bacterium before its resistance spreads to even deadlier organisms.
The increase in drug resistance among medically important bacteria has led to an interest in the development of novel drug candidates, especially those with efficacy against multiple drug resistant (MDR) infectious agents. Over the past 60 years, between 30,000 and 50,000 natural products have been derived from microorganisms, mainly soil-derived bacteria and fungi. More than 10,000 of these compounds are biologically active, the majority of which are antibiotics and anti-tumor agents. Although soil bacteria continue to be studied extensively, with the goal of discovering other novel anti-bacterial agents, it is clear that the rate of discovery for novel antibacterial agents is decreasing. Therefore, scientists have begun to evaluate new sources of bioactive natural products, in hopes of discovering other effective pharmacologically-active agents.
Oceans compose over 70% of the earth's surface and over 90% of the volume of its crust. Microbiologically, the oceans are massively complex and contain a diverse group of lifeforms. Indeed, marine microorganisms have developed unique physiological capabilities to survive in an environment of extreme variation in pressure, salinity, and temperature. Thus, these microorganisms offer the potential for the production of metabolites which may not be observed in the more familiar soil-derived microorganisms.
Previously, microorganisms isolated from seawater have been shown to produce compounds and metabolites with effective antibiotic activity. The first such molecules to be isolated were highly brominated pyrroles, but these compounds were not effective against Gram-negative bacteria. However, tetrabromopyrrole, isolated from a marine organism of the Altermonas genus, was shown to be effective against other marine bacteria.
Other investigators found that certain marine pseudomonads also produce antibiotics, such as 2-n-pentylquinolinol, which exhibits activity against Vibrio harveyi. Similarly, a Pseudomonas species isolated from tropical green algae produces two antibiotic "pigments," known as magnesidins. Finally, a seawater-derived bacterium of unknown identity was found to produce a new lactone, oncorhynoclide, which inhibited various test organisms.
Microbes isolated from marine sediments have also been shown to produce pharmacologically-active antibiotics, and almost all of these organisms belong to the Order Actinomycetales. Many antibiotic-producing terrestrial strains also belong to this Order, of which the genus Streptomyces is the best known member. Common antibiotics like Chloramphenicol, Novobiocin, and Bacitracin also were originally derived from terrestrial microorganisms.
Currently, scientists are examining other marine and terrestrial species to identify novel compounds which exhibit antibiotic activity. Because of the alarming increase in drug resistance already noted, there is a pressing need for the development of such novel antimicrobials, especially those exhibiting efficacy against multiple drug-resistant organisms.