Commonly Used Antimicrobial Drugs

Synthetic Antimicrobial Drugs

An antimicrobial is a substance that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans.

Learning Objectives

Recall the synthetic antimicrobial drugs that are sulfonamide and sulphonamide based

Key Takeaways

Key Points

  • The discovery of antimicrobials like penicillin and tetracycline paved the way for better health for millions around the world.
  • With the development of antimicrobials, microorganisms have adapted and become resistant to previous antimicrobial agents.
  • Synthetic agents include: sulphonamides, cotrimoxazole, quinolones, anti-virals, anti-fungals, anti-cancer drugs, anti-malarials, anti-tuberculosis drugs, anti-leprotics, and anti-protozoals.

Key Terms

  • antimicrobial: An agent that destroys microbes, inhibits their growth, or prevents or counteracts their pathogenic action.
  • microorganism: An organism that is too small to be seen by the unaided eye, especially a single-celled organism, such as a bacterium.
  • bacteria: A type, species, or strain of bacterium.

An antimicrobial is a substance that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans. Antimicrobial drugs either kill microbes (microbiocidal) or prevent the growth of microbes (microbiostatic). Disinfectants are antimicrobial substances used on non-living objects or outside the body.

The history of antimicrobials begins with the observations of Pasteur and Joubert, who discovered that one type of bacteria could prevent the growth of another. They did not know at that time that the reason one bacterium failed to grow was that the other bacterium was producing an antibiotic. Technically, antibiotics are only those substances that are produced by one microorganism that kill, or prevent the growth, of another microorganism. Of course, in today’s common usage, the term antibiotic is used to refer to almost any drug that attempts to rid your body of a bacterial infection. Antimicrobials include not just antibiotics, but synthetically formed compounds as well.

The discovery of antimicrobials like penicillin and tetracycline paved the way for better health for millions around the world. Before penicillin became a viable medical treatment in the early 1940s, no true cure for gonorrhea, strep throat, or pneumonia existed. Patients with infected wounds often had to have a wounded limb removed, or face death from infection. Now, most of these infections can be cured easily with a short course of antimicrobials.

However, with the development of antimicrobials, microorganisms have adapted and become resistant to previous antimicrobial agents. The old antimicrobial technology was based either on poisons or heavy metals, which may not have killed the microbe completely, allowing the microbe to survive, change, and become resistant to the poisons and/or heavy metals.

Antimicrobial nanotechnology is a recent addition to the fight against disease-causing organisms, replacing heavy metals and toxins, and may some day be used as a viable alternative.

Infections that are acquired during a hospital visit are called “hospital acquired infections” or nosocomial infections. Similarly, when the infectious disease is picked up in the non-hospital setting, it is considered “community acquired”.

Synthetic agents include: sulphonamides, cotrimoxazole, quinolones, anti-virals, anti-fungals, anti-cancer drugs, anti-malarials, anti-tuberculosis drugs, anti-leprotics, and anti-protozoals.

Sulfonamide or sulphonamide is the basis of several groups of drugs. The original antibacterial sulfonamides (sometimes called sulfa drugs or sulpha drugs) are synthetic antimicrobial agents that contain the sulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g., the anticonvulsant sultiame. The sulfonylureas and thiazide diuretics are newer drug groups based on the antibacterial sulfonamides.

Sulfa allergies are common, and medications containing sulfonamides are prescribed carefully. It is important to make a distinction between sulfa drugs and other sulfur-containing drugs and additives, such as sulfates and sulfites, which are chemically unrelated to the sulfonamide group and do not cause the same hypersensitivity reactions seen in the sulfonamides.

In bacteria, antibacterial sulfonamides act as competitive inhibitors of the enzyme dihydropteroate synthetase (DHPS), an enzyme involved in folate synthesis. As such, the microorganism will be “starved” of folate and die.

The sulfonamide chemical moiety is also present in other medications that are not antimicrobials, including thiazide diuretics (including hydrochlorothiazide, metolazone, and indapamide, among others), loop diuretics (including furosemide, bumetanide, and torsemide), sulfonylureas (including glipizide, glyburide, among others), and some COX-2 inhibitors (e.g., celecoxib), and acetazolamide.

Naturally Occurring Antimicrobial Drugs: Antibiotics

An antimicrobial is a substance that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans.

Learning Objectives

Discuss the mechanism of action for protein synthesis inhibitors used as antimicrobial drugs, and recognize various naturally occuring antimicrobial drugs

Key Takeaways

Key Points

  • There are mainly two classes of antimicrobial drugs: those obtained from natural sources (i.e. beta-lactam antibiotic (such as penicillins, cephalosporins) or protein synthesis inhibitors (such as aminoglycosides, macrolides, tetracyclines, chloramphenicol, polypeptides); and synthetic agents.
  • A β-lactam (beta-lactam) ring is a four-membered lactam. A lactam is a cyclic amide. It is named as such because the nitrogen atom is attached to the β-carbon relative to the carbonyl.
  • A protein synthesis inhibitor is a substance that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins.

Key Terms

  • β-lactam: A β-lactam (beta-lactam) ring is a four-membered lactam. A lactam is a cyclic amide. It is named as such, because the nitrogen atom is attached to the β-carbon relative to the carbonyl. The simplest β-lactam possible is 2-azetidinone.
  • antimicrobial: An agent that destroys microbes, inhibits their growth, or prevents or counteracts their pathogenic action.
  • microorganism: An organism that is too small to be seen by the unaided eye, especially a single-celled organism, such as a bacterium.

An antimicrobial is a substance that kills or inhibits the growth of microorganisms bacteria, fungi, or protozoans. Antimicrobial drugs either kill microbes (microbiocidal) or prevent the growth of microbes (microbiostatic). Disinfectants are antimicrobial substances used on non-living objects or outside the body.

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A cluster of Escherichia coli Bacteria magnified 10,000 times.: A cluster of Escherichia coli Bacteria magnified 10,000 times.

The discovery of antimicrobials, like penicillin and tetracycline, paved the way for better health for millions of people around the world. Before penicillin became a viable medical treatment in the early 1940’s, no true cure for gonorrhea, strep throat, or pneumonia existed. Patients with infected wounds often had to have a wounded limb removed or face death from infection. Now, most of these infections can be cured easily with a short course of antimicrobials.

However, with the development of antimicrobials, microorganisms have adapted and become resistant to previous antimicrobial agents. The old antimicrobial technology was based either on poisons or heavy metals, which may not have killed the microbe completely. This allowed the microbe to survive, change, and become resistant to the poisons and/or heavy metals.

Antimicrobial nanotechnology is a recent addition to the fight against disease causing organisms. It replaces heavy metals and toxins and may someday be a viable alternative.

Infections that are acquired during a hospital visit are called “hospital acquired infections” or nosocomial infections. Similarly, when the infectious disease is picked up in the non-hospital setting it is considered “community acquired. ”

There are mainly two classes of antimicrobial drugs: those obtained from natural sources (i.e. beta-lactam) antibiotic (such as penicillins, cephalosporins) or protein synthesis inhibitors (such as aminoglycosides, macrolides, tetracyclines, chloramphenicol, polypeptides); and synthetic agents.

A β-lactam (beta-lactam) ring is a four-membered lactam. A lactam is a cyclic amide. It is named as such, because the nitrogen atom is attached to the β-carbon relative to the carbonyl. The simplest β-lactam possible is 2-azetidinone.

A protein synthesis inhibitor is a substance that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins. While a broad interpretation of this definition could be used to describe nearly any antibiotic, in practice, it usually refers to substances that act at the ribosome level (either the ribosome itself or the translation factor), taking advantage of the major differences between prokaryotic and eukaryotic ribosome structures. Toxins such as ricin also function via protein synthesis inhibition. Ricin acts at the eukaryotic 60S.

In general, protein synthesis inhibitors work at different stages of prokaryotic mRNA translation into proteins, like initiation, elongation (including aminoacyl tRNA entry, proofreading, peptidyl transfer, and ribosomal translocation), and termination. Rifamycin inhibits prokaryotic DNA transcription into mRNA by inhibiting DNA-dependent RNA polymerase by binding its beta-subunit. Linezolid acts at the initiation stage probably by preventing the formation of the initiation complex, although the mechanism is not fully understood.

Tetracyclines and Tigecycline (a glycylcycline related to tetracyclines) block the A site on the ribosome, preventing the binding of aminoacyl tRNAs. Aminoglycosides, among other potential mechanisms of action, interfere with the proofreading process, causing increased rate of error in synthesis with premature termination. Chloramphenicol blocks the peptidyl transfer step of elongation on the 50S ribosomal subunit in both bacteria and mitochondria. Macrolides (as well as inhibiting ribosomal translocation and other potential mechanisms) bind to the 50s ribosomal subunits, inhibiting peptidyl transfer. Quinupristin/dalfopristin act synergistically, with dalfopristin, enhancing the binding of quinupristin as well as inhibiting peptidyl transfer. Quinupristin binds to a nearby site on the 50S ribosomal subunit and prevents elongation of the polypeptide. It also causes incomplete chains to be released. Macrolides, clindamycin, and aminoglycosides (with all these three having other potential mechanisms of action as well) have evidence of inhibition of ribosomal translocation. Fusidic acid prevents the turnover of elongation factor G (EF-G) from the ribosome. Macrolides and clindamycin (both also having other potential mechanisms) cause premature dissociation of the peptidyl-tRNA from the ribosome. Puromycin has a structure similar to that of the tyrosinyl aminoacyl-tRNA. Therefore, it binds to the ribosomal A site and participates in peptide bond formation, producing peptidyl-puromycin. However, it does not engage in translocation and quickly dissociates from the ribosome, causing a premature termination of polypeptide synthesis.

Beta-Lactam Antibiotics: Penicillins and Cephalosporins

The β-lactam ring is part of the core structure of several antibiotic families.

Learning Objectives

Recognize the classes of beta-lactams and their mechanisms of action

Key Takeaways

Key Points

  • The principal antibiotic families of which the β-lactam ring is part of the core structure are the penicillins, cephalosporins, carbapenems, and monobactams, which are also called β-lactam antibiotics.
  • A β-lactam (beta-lactam) ring is a four-membered lactam (cyclic amide). -Lactams are classified according to their core ring structures.
  • The cephalosporins are a class of β-lactam antibiotics originally derived from the fungus Acremonium, which was previously known as “Cephalosporium”.

Key Terms

  • cephalosporins: The cephalosporins are a class of β-lactam antibiotics originally derived from the fungus Acremonium, which was previously known as “Cephalosporium”.
  • antibiotic: Any substance that can destroy or inhibit the growth of bacteria and similar microorganisms.
  • β-lactam: A β-lactam (beta-lactam) ring is a four-membered lactam. A lactam is a cyclic amide. It is named as such, because the nitrogen atom is attached to the β-carbon relative to the carbonyl. The simplest β-lactam possible is 2-azetidinone.
  • β-lactam: Any of a class of cyclic amides, that are the nitrogen analogs of lactones, formed by heating amino acids; the tautomeric enol forms are known as lactims.

A β-lactam (beta-lactam) ring, is a four-membered lactam. It is named as such, because the nitrogen atom is attached to the β-carbon relative to the carbonyl. The simplest β-lactam possible is 2-azetidinone.

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β-Lactam: β-Lactam ring is a four-membered lactam.

The β-lactam ring is part of the core structure of several antibiotic families, the principal ones being the penicillins, cephalosporins, carbapenems, and monobactams, which are, therefore, also called β-lactam antibiotics. Nearly all of these antibiotics work by inhibiting bacterial cell wall biosynthesis. This has a lethal effect on bacteria. Bacteria do, however, contain within their populations, in smaller quantities, bacteria that are resistant against β-lactam antibiotics. They do this by expressing the β-lactamase gene. When bacterial populations have these resistant subgroups, treatment with β-lactam can result in the resistant strain becoming more prevalent and so, more virulent.

β-Lactams are classified according to their core ring structures:

  • β-Lactams fused to saturated five-membered rings;
  • β-Lactams containing thiazolidine rings are named penams;
  • β-Lactams containing pyrrolidine rings are named carbapenams;
  • β-Lactams fused to oxazolidine rings are named oxapenams or clavams;
  • β-Lactams fused to unsaturated five-membered rings;
  • β-Lactams containing 2,3-dihydrothiazole rings are named penems;
  • β-Lactams containing 2,3-dihydro-1H-pyrrole rings are named carbapenems;
  • β-Lactams fused to unsaturated, six-membered rings;
  • β-Lactams containing 3,6-dihydro-2H-1,3-thiazine rings are named cephems;
  • β-Lactams containing 1,2,3,4-tetrahydropyridine rings are named carbacephems;
  • β-Lactams containing 3,6-dihydro-2H-1,3-oxazine rings are named oxacephems; and
  • β-Lactams not fused to any other ring are named monobactams.

Penicillin (sometimes abbreviated PCN or pen) is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V. Penicillin antibiotics are historically significant because they are the first drugs that were effective against many previously serious diseases, such as syphilis, and infections caused by staphylococci and streptococci. Penicillins are still widely used today, though many types of bacteria are now resistant. All penicillins are β-lactam antibiotics and are used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms.

The cephalosporins (sg. /ˌsɛfəlɵspɔrɨn/) are a class of β-lactam antibiotics originally derived from the fungus Acremonium, which was previously known as “Cephalosporium”. Together with cephamycins, they constitute a subgroup of β-lactam antibiotics called cephems. Cephalosporins are indicated for the prophylaxis and treatment of infections caused by bacteria susceptible to this particular form of antibiotic. First-generation cephalosporins are active predominantly against Gram-positive bacteria, and successive generations have increased activity against Gram-negative bacteria (albeit often with reduced activity against Gram-positive organisms).

Antibiotics from Prokaryotes

Most of the currently available antibiotics are produced by prokaryotes mainly by bacteria from the genus Streptomyces.

Learning Objectives

Explain the role of Streptomyces and other prokaryotes in antibiotic production

Key Takeaways

Key Points

  • Gramicidin is one of the first antibiotics to be manufactured commercially. It is a heterogeneous mixture of six antibiotic compounds, all of which are obtained from the soil bacterial species Bacillus brevis.
  • Streptomyces is the largest antibiotic-producing genus, producing antibacterial, antifungal, and antiparasitic drugs, and also a wide range of other bioactive compounds, such as immunosuppressants. They produce over two-thirds of the clinically useful antibiotics of natural origin.
  • Members of the Streptomyces genus are the source for numerous antibacterial pharmaceutical agents; among the most important of these are: Chloramphenicol (from S. venezuelae), Lincomycin (from S. lincolnensis), Neomycin (from S. fradiae), Tetracycline (from S. rimosus and S. aureofaciens).
  • Some Pseudomonas spp. might produce compounds antagonistic to other soil microbes, such as phenazine-type antibiotics or hydrogen cyanide.

Key Terms

  • antibiotic: Any substance that can destroy or inhibit the growth of bacteria and similar microorganisms.
  • beta-lactamase: An enzyme produced by certain bacteria, responsible for their resistance to beta-lactam antibiotics such as penicillin.

Even though penicillin drugs, antibiotics produced by molds, were the first antibiotics successfully used to treat many serious infections, most of the naturally produced antibiotics are synthesized by bacteria. In 1939 the French microbiologist René Dubos isolated the substance tyrothricin and later showed that it was composed of two substances, gramicidin (20%) and tyrocidine (80%). These were the first antibiotics to be manufactured commercially. Gramicidin is a heterogeneous mixture of six antibiotic compounds, all of which are obtained from the soil bacterial species Bacillus brevis and called collectively gramicidin D.

Streptomyces is the largest antibiotic-producing genus, producing antibacterial, antifungal, and antiparasitic drugs, and also a wide range of other bioactive compounds, such as immunosuppressants. They produce over two-thirds of the clinically useful antibiotics of natural origin. The now uncommonly-used streptomycin takes its name directly from Streptomyces. Aminoglycosides, class of antibiotics, that are derived from bacteria of the Streptomyces genus are named with the suffix -mycin, whereas those that are derived from Micromonospora are named with the suffix -micin. However, this nomenclature system is not specific for aminoglycosides.

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Supernatant of a Streptomyces davawensis culture: The picture shows the typical red color of the antibiotic Roseoflavin secreted by the Streptomyces cells in the culture.

Streptomycetes are characterised by a complex secondary metabolism. Almost all of the bioactive compounds produced by Streptomyces are initiated during the time coinciding with the aerial hyphal formation from the substrate mycelium.

Streptomycetes produce numerous antifungal compounds of medicinal importance, including nystatin (from S. noursei), amphotericin B (from S. nodosus), and natamycin (from S. natalensis).

Members of the Streptomyces genus are the source for numerous antibacterial pharmaceutical agents; among the most important of these are: Chloramphenicol (from S. venezuelae), Daptomycin (from S. roseosporus), Fosfomycin (from S. fradiae), Lincomycin (from S. lincolnensis), Neomycin (from S. fradiae), Puromycin (from S. alboniger), Streptomycin (from S. griseus), Tetracycline (from S. rimosus and S. aureofaciens).

Clavulanic acid (from S. clavuligerus) is a drug used in combination with some antibiotics (like amoxicillin) to block and/or weaken some bacterial-resistance mechanisms by irreversible beta-lactamase inhibition.

Other bacterial species produce antibiotics as well. Such an example are some Pseudomonas species which produce antimicrobial compounds. P. aurantiaca produces di-2,4-diacetylfluoroglucylmethane, a compound antibiotically active against Gram-positive organisms. Other Pseudomonas spp. might produce compounds antagonistic to other soil microbes, such as phenazine-type antibiotics or hydrogen cyanide.

Antimycobacterial Antibiotics

Antimycobacterial antibiotics target microbes classified as mycobacterium.

Learning Objectives

Compare and contrast the drugs used for treatment of Mycobacterium tuberculosis and Mycobacterium leprae

Key Takeaways

Key Points

  • The standard “short” course treatment for TB is isoniazid, rifampicin, pyrazinamide, and ethambutol for two months, then isoniazid and rifampicin alone for another four months.
  • The standard treatment for leprosy is a multidrug therapy that includes dapsone, clofazimine and rifampicin.
  • Mycobacterium are defined by their ability to grow in a mold-like fashion on the surface of liquids when cultured.

Key Terms

  • tuberculosis: Tuberculosis, MTB, or TB (short for tubercle bacillus) is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis.
  • infectious disease: Infectious diseases, also known as transmissible diseases or communicable diseases comprise of clinically evident illness (i.e., characteristic medical signs and/or symptoms of disease) resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism. In certain cases, infectious diseases may be asymptomatic for much or even all of their course in a given host. In the latter case, the disease may only be defined as a “disease” (which by definition means an illness) in hosts who secondarily become ill after contact with an asymptomatic carrier. An infection is not synonymous with an infectious disease, as some infections do not cause illness in a host.
  • leprosy: Leprosy, also known as Hansen’s disease (HD), is a chronic disease caused by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis.
  • isoniazid: a medication used in the prevention and treatment of tuberculosis, having the chemical formula C6H7N3O

Antimycobacterial antibiotics are a class of antimicrobial drugs that target mycobacterium. Mycobacterium is a genus of Actinobacteria that includes pathogens known to cause serious and infectious disease. The types of pathogens considered to be mycobacterium include Mycobacterium tuberculosis (tuberculosis) and Mycobacterium leprae (leprosy). Mycobacterium grow in a mold-like manner on the surface of liquids when cultured. Antiomycobacterial antibiotics specifically target these types of microbes.

A type of antimycobacterial antibiotic includes the class of drugs used for tuberculosis (TB) treatment. The standard “short” course treatment for TB is isoniazid, rifampicin (also known as rifampin in the United States), pyrazinamide and ethambutol for two months, then isoniazid and rifampicin alone for another four months. The patient is considered cured at six months (although there is still a relapse rate of 2 to 3%). For latent tuberculosis, the standard treatment is six to nine months of isoniazid alone.

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Mycobacterium: Mycobacterium are a class of bacteria defined by their ability to grow in a mold-like manner. Here, a TEM of Mycobacterium tuberculosis, the causative agent of tuberculosis. Antimycobacterial antibiotics target mycobacterium.

If the organism is known to be fully sensitive, then it is treated with isoniazid, rifampicin and pyrazinamide for two months, followed by isoniazid and rifampicin for four months. Ethambutol need not be used. Most regimens have an initial high-intensity phase, followed by a continuation phase (also called a consolidation phase or eradication phase) – the high-intensity phase is given first, then the continuation phase.

There are six classes of second-line drugs (SLDs) used for the treatment of TB. A drug may be classed as second-line instead of first-line for one of three possible reasons: it may be less effective than the first-line drugs (e.g., p-aminosalicylic acid); or, it may have toxic side-effects (e.g., cycloserine); or it may be unavailable in many developing countries (e.g., fluoroquinolones): aminoglycosides: e.g., amikacin (AMK), kanamycin (KM); polypeptides: e.g., capreomycin, viomycin, enviomycin; Fluoroquinolones: e.g., ciprofloxacin (CIP), levofloxacin, moxifloxacin (MXF); thioamides: e.g. ethionamide, prothionamide.

For treatment of leprosy, caused by Mycobacterium leprae, the traditional antimycobacterial drugs include promin (the first treatment introduced to fight leprosy) and dapsone (which eventually become obsolete as Mycobacterium leprae quickly evolved resistance). Modern drugs which were developed in response to the resistance was clofazimine and rifampicin. The use of multidrug therapies including dapsone, clofazimine and rifampicin were advantageous due to the low risk of antibiotic resistance. However, the use of these multidrug treatments was costly and only adopted in endemic countries when the World Health Assembly passed a resolution to eliminate leprosy in 1991.