14.1: Discovering Antimicrobial Drugs - Biology

14.1: Discovering Antimicrobial Drugs - Biology

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Learning Objectives

  • Compare and contrast natural, semisynthetic, and synthetic antimicrobial drugs
  • Describe the chemotherapeutic approaches of ancient societies
  • Describe the historically important individuals and events that led to the development of antimicrobial drugs

Clinical Note: PART 1

Marisa, a 52-year-old woman, was suffering from severe abdominal pain, swollen lymph nodes, fatigue, and a fever. She had just returned home from visiting extended family in her native country of Cambodia. While abroad, she received medical care in neighboring Vietnam for a compressed spinal cord. She still had discomfort when leaving Cambodia, but the pain increased as her trip home continued and her husband drove her straight from the airport to the emergency room.

Her doctor considers whether Marisa could be suffering from appendicitis, a urinary tract infection (UTI), or pelvic inflammatory disease (PID). However, each of those conditions is typically preceded or accompanied by additional symptoms. He considers the treatment she received in Vietnam for her compressed spinal cord, but abdominal pain is not usually associated with spinal cord compression. He examines her health history further.

Exercise (PageIndex{1})

  1. What type of infection or other condition may be responsible?
  2. What type of lab tests might the doctor order?

Most people associate the term chemotherapy with treatments for cancer. However, chemotherapy is actually a broader term that refers to any use of chemicals or drugs to treat disease. Chemotherapy may involve drugs that target cancerous cells or tissues, or it may involve antimicrobial drugs that target infectious microorganisms. Antimicrobial drugs typically work by destroying or interfering with microbial structures and enzymes, either killing microbial cells or inhibiting of their growth. But before we examine how these drugs work, we will briefly explore the history of humans’ use of antimicrobials for the purpose of chemotherapy.

Use of Antimicrobials in Ancient Societies

Although the discovery of antimicrobials and their subsequent widespread use is commonly associated with modern medicine, there is evidence that humans have been exposed to antimicrobial compounds for millennia. Chemical analyses of the skeletal remains of people from Nubia1 (now found in present-day Sudan) dating from between 350 and 550 AD have shown residue of the antimicrobial agent tetracycline in high enough quantities to suggest the purposeful fermentation of tetracycline-producing Streptomyces during the beer-making process. The resulting beer, which was thick and gruel-like, was used to treat a variety of ailments in both adults and children, including gum disease and wounds. The antimicrobial properties of certain plants may also have been recognized by various cultures around the world, including Indian and Chinese herbalists (Figure (PageIndex{1})) who have long used plants for a wide variety of medical purposes. Healers of many cultures understood the antimicrobial properties of fungi and their use of moldy bread or other mold-containing products to treat wounds has been well documented for centuries.2 Today, while about 80% of the world’s population still relies on plant-derived medicines,3 scientists are now discovering the active compounds conferring the medicinal benefits contained in many of these traditionally used plants.

Exercise (PageIndex{2})

Give examples of how antimicrobials were used in ancient societies

The First Antimicrobial Drugs

Societies relied on traditional medicine for thousands of years; however, the first half of the 20th century brought an era of strategic drug discovery. In the early 1900s, the German physician and scientist Paul Ehrlich (1854–1915) set out to discover or synthesize chemical compounds capable of killing infectious microbes without harming the patient. In 1909, after screening more than 600 arsenic-containing compounds, Ehrlich’s assistant Sahachiro Hata (1873–1938) found one such “magic bullet.” Compound 606 targeted the bacterium Treponema pallidum, the causative agent of syphilis. Compound 606 was found to successfully cure syphilis in rabbits and soon after was marketed under the name Salvarsan as a remedy for the disease in humans (Figure (PageIndex{2})). Ehrlich’s innovative approach of systematically screening a wide variety of compounds remains a common strategy for the discovery of new antimicrobial agents even today.

A few decades later, German scientists Josef Klarer, Fritz Mietzsch, and Gerhard Domagk discovered the antibacterial activity of a synthetic dye, prontosil, that could treat streptococcal and staphylococcal infections in mice. Domagk’s own daughter was one of the first human recipients of the drug, which completely cured her of a severe streptococcal infection that had resulted from a poke with an embroidery needle. Gerhard Domagk (1895–1964) was awarded the Nobel Prize in Medicine in 1939 for his work with prontosil and sulfanilamide, the active breakdown product of prontosil in the body. Sulfanilamide, the first synthetic antimicrobial created, served as the foundation for the chemical development of a family of sulfa drugs. A synthetic antimicrobial is a drug that is developed from a chemical not found in nature. The success of the sulfa drugs led to the discovery and production of additional important classes of synthetic antimicrobials, including the quinolines and oxazolidinones.

A few years before the discovery of prontosil, scientist Alexander Fleming (1881–1955) made his own accidental discovery that turned out to be monumental. In 1928, Fleming returned from holiday and examined some old plates of staphylococci in his research laboratory at St. Mary’s Hospital in London. He observed that contaminating mold growth (subsequently identified as a strain of Penicillium notatum) inhibited staphylococcal growth on one plate. Fleming, therefore, is credited with the discovery of penicillin, the first natural antibiotic, (Figure (PageIndex{3})). Further experimentation showed that penicillin from the mold was antibacterial against streptococci, meningococci, and Corynebacterium diphtheriae, the causative agent of diphtheria.

Fleming and his colleagues were credited with discovering and identifying penicillin, but its isolation and mass production were accomplished by a team of researchers at Oxford University under the direction of Howard Florey(1898–1968) and Ernst Chain (1906–1979) (Figure (PageIndex{3})). In 1940, the research team purified penicillin and reported its success as an antimicrobial agent against streptococcal infections in mice. Their subsequent work with human subjects also showed penicillin to be very effective. Because of their important work, Fleming, Florey, and Chain were awarded the Nobel Prize in Physiology and Medicine in 1945.

In the early 1940s, scientist Dorothy Hodgkin (1910–1994), who studied crystallography at Oxford University, used X-rays to analyze the structure of a variety of natural products. In 1946, she determined the structure of penicillin, for which she was awarded the Nobel Prize in Chemistry in 1964. Once the structure was understood, scientists could modify it to produce a variety of semisynthetic penicillins. A semisynthetic antimicrobial is a chemically modified derivative of a natural antibiotic. The chemical modifications are generally designed to increase the range of bacteria targeted, increase stability, decrease toxicity, or confer other properties beneficial for treating infections.

Penicillin is only one example of a natural antibiotic. Also in the 1940s, Selman Waksman (1888–1973) (Figure (PageIndex{4})), a prominent soil microbiologist at Rutgers University, led a research team that discovered several antimicrobials, including actinomycin, streptomycin, and neomycin. The discoveries of these antimicrobials stemmed from Waksman’s study of fungi and the Actinobacteria, including soil bacteria in the genus Streptomyces, known for their natural production of a wide variety of antimicrobials. His work earned him the Nobel Prize in Physiology and Medicine in 1952. The actinomycetes are the source of more than half of all natural antibiotics4 and continue to serve as an excellent reservoir for the discovery of novel antimicrobial agents. Some researchers argue that we have not yet come close to tapping the full antimicrobial potential of this group.5

Exercise (PageIndex{3})

Why is the soil a reservoir for antimicrobial resistance genes?

Key Concepts and Summary

  • Antimicrobial drugs produced by purposeful fermentation and/or contained in plants have been used as traditional medicines in many cultures for millennia.
  • The purposeful and systematic search for a chemical “magic bullet” that specifically target infectious microbes was initiated by Paul Ehrlich in the early 20th century.
  • The discovery of the natural antibiotic, penicillin, by Alexander Fleming in 1928 started the modern age of antimicrobial discovery and research.
  • Sulfanilamide, the first synthetic antimicrobial, was discovered by Gerhard Domagk and colleagues and is a breakdown product of the synthetic dye, prontosil.


  1. 1 M.L. Nelson et al. “Brief Communication: Mass Spectroscopic Characterization of Tetracycline in the Skeletal Remains of an Ancient Population from Sudanese Nubia 350–550 CE.” American Journal of Physical Anthropology 143 no. 1 (2010):151–154.
  2. 2 M. Wainwright. “Moulds in Ancient and More Recent Medicine.” Mycologist 3 no. 1 (1989):21–23.
  3. 3 S. Verma, S.P. Singh. “Current and Future Status of Herbal Medicines.” Veterinary World 1 no. 11 (2008):347–350.
  4. 4 J. Berdy. “Bioactive Microbial Metabolites.” The Journal of Antibiotics 58 no. 1 (2005):1–26.
  5. 5 M. Baltz. “Antimicrobials from Actinomycetes: Back to the Future.” Microbe 2 no. 3 (2007):125–131.

Penicillin's Discovery and Antibiotic Resistance: Lessons for the Future?

Undoubtedly, the discovery of penicillin is one of the greatest milestones in modern medicine. 2016 marks the 75th anniversary of the first systemic administration of penicillin in humans, and is therefore an occasion to reflect upon the extraordinary impact that penicillin has had on the lives of millions of people since. This perspective presents a historical account of the discovery of the wonder drug, describes the biological nature of penicillin, and considers lessons that can be learned from the golden era of antibiotic research, which took place between the 1940s and 1960s. Looking back at the history of penicillin might help us to relive this journey to find new treatments and antimicrobial agents. This is particularly relevant today as the emergence of multiple drug resistant bacteria poses a global threat, and joint efforts are needed to combat the rise and spread of resistance.

Keywords: Howard Florey Penicillin antimicrobial resistance.

Antimicrobial Drugs: Features and Mechanisms | Microbiology

In this article we will discuss about the features and mechanisms of antimicrobial drugs.

Features of Antimicrobial Drugs:

Some of the features of antimicrobial drugs are given below:

(a) Antibiotics are biologically active against a large number of organisms even in extremely low concentration. It is interesting to observe that 0.000001 g/ml of penicillin G has a pronounced effect on bacteria sensitive to this antibiotic.

Therefore, the minimal inhibitory concentration (MIC) of an antibiotics effective against different microorganisms, or MIC of different microorganisms for a given microbe differs. MIC refers to the lowest concentration of drugs required to kill the microbial pathogen. It is also called minimal lethal concentration.

(b) These are very selective in posing toxicity i.e. they must kill or inhibit the pathogenic microbe without having harmful effect, or having least harm to the host. This is called selective toxicity. For example penicillin acts against Gram-positive bacteria (e.g. streptococci), while streptomycin acts against Gram-negative bacteria e.g. E. coli.

(c) The degree of selective toxicity is expressed in terms of therapeutic index which is the ratio of toxic dose to the therapeutic dose. The therapeutic dose is the drug level required for treatment of a particular infection, while the toxic dose is amount of drug at which it becomes too toxic to the host.

(d) The range of effectiveness of antimicrobial drugs varies. These may be narrow-spectrum drugs (effective only against a limited number of pathogens), or broad-spectrum drugs (effective against a large number of pathogenic microbes).

However, on the basis of groups of microorganisms, the antimicrobial drugs are also classified as antibacterial (effective against bacteria), antifungal (against fungi), anti-protozoan (against protozoan) and antiviral (against viruses).

(e) Antibiotics are secondary metabolites i.e. they are not required during the growth by microorganisms. Therefore, these accumulate either inside the cell or secreted outside the cell. Some of the antibiotics are volatile as well. In recent years, the natural molecule of the antibiotics are being chemically or biologically modified, and new ones being produced.

Such modified antibiotics are known as semisynthetic antibiotics e.g. ampicillin, methicillin, carbenicillin, etc. The semisyn­thetic antibiotics are more important as compared to natural antibiotics. Thus, the semisynthetic antibiotics are natural antibiotics that have been chemically modified by the addition of extra chemical group so that it could not be inactivated by pathogens.

(f) The potency of antibiotics is normally expressed in terms of units/ml or solution or in one milligram [U (units)/mg]. After the discovery of antibiotics it was found that 1 mg of streptomycin is equivalent to 1000 units. Now-a-days the antibiotic vials’ label shows the quantity expressed in terms of weight as well as activity. For example, 1 mg of the penicillin G (benzyl-penicillin) is equivalent to 1667 units.

Mechanism of Action of Antimicrobial Drugs:

After administration of antimicrobial drugs against a particular pathogen, a patient feels relief. This is due to killing of infectious microorganisms involved with a specific disease. It is interesting to know how does it act? The mechanism of action of each antimicrobial drug differs.

However, on the basis of their mode of action, it can be grouped as below:

(i) Inhibition in Synthesis of Bacterial Cell Wall:

Penicillins stop the synthesis of cell wall of Gram-positive bacteria that are synthesizing new peptidoglycan. It inhibits trans-peptide enzymes which are responsible for cross-linking of the polypeptide chain of the bacterial cell wall peptidoglycan. It also activates cell wall lytic enzymes. The other antibiotics that inhibit cell wall of bacteria are ampicillin, carbenicillin, methicillin, bacitracin, vancomycin, cephalosporin, etc.

(ii) Disruption of Cell Wall:

Polymyxin B binds to plasma membrane and disrupts its structure and properties of permeability.

(iii) Alteration in Membrane Function:

Gramicidin can alter the function of cell membrane. The dis-organisation of the state and function have been well noticed. It brings about changes in permeability of cell membrane and causes a quick loss of amino acids, minerals, phosphorus and nucleotides. Also it inhibits the energy metabolism bringing about alteration in permeability e.g. polymyxin, nystatin, etc.

(iv) Inhibition in Protein Synthesis:

Protein synthesis is the universal phenomenon of a living cell. However, some antibiotics inhibit protein synthesis of pathogenic microorganisms and act differently. Streptomycin binds to 30S subunit of the bacterial ribosome and cause misreading of mRNA and, therefore, inhibits protein synthesis at the final stage (i.e. during transport of aminoacyl tRNA to ribosomes.

However, it does not affect the initial stage i.e. activation of amino acids. Similar is the effect of gentamycin and tetracycline. Chloramphenicol and erythromycin bind to SOS ribosomal subunit and inhibits peptide chain formation and elongation respectively by inhibiting peptidyl transferase.

(v) Inhibition in Synthesis of Purines and Pyrimidines:

Mitomycin C inhibits the growth of many bacteria, protozoa, etc. and arrests the growth of tumour cells. The chromatophore of actinomycin is incorporated between DNA base pairs, whereas mitamycin blocks the synthesis of DNA without affecting RNA and protein synthesis. Rifampicin inhibits DNA-dependent RNA polymerase and, therefore, blocks protein synthesis.

(vi) Inhibition in Respiration:

Antimycins inhibit the growth of some fungi. This group of antibiotics inhibit oxidation of succinate. Valinomycin is active against Gram-positive bacteria and inhibits oxidative phosphorylation. Gramicidins are inhibitors of phosphorylation.

(vii) Antagonism of Metabolic Pathways:

There are some of the antibiotics that block the functioning of metabolic pathways through competitive inhibition of key enzymes. Such valuable drugs are known as antimetabolites.

Multiple Choice

A scientist discovers that a soil bacterium he has been studying produces an antimicrobial that kills gram-negative bacteria. She isolates and purifies the antimicrobial compound, then chemically converts a chemical side chain to a hydroxyl group. When she tests the antimicrobial properties of this new version, she finds that this antimicrobial drug can now also kill gram-positive bacteria. The new antimicrobial drug with broad-spectrum activity is considered to be which of the following?

Which of the following antimicrobial drugs is synthetic?

Which of the following combinations would most likely contribute to the development of a superinfection?

  1. long-term use of narrow-spectrum antimicrobials
  2. long-term use of broad-spectrum antimicrobials
  3. short-term use of narrow-spectrum antimicrobials
  4. short-term use of broad-spectrum antimicrobials

Which of the following routes of administration would be appropriate and convenient for home administration of an antimicrobial to treat a systemic infection?

Which clinical situation would be appropriate for treatment with a narrow-spectrum antimicrobial drug?

  1. treatment of a polymicrobic mixed infection in the intestine
  2. prophylaxis against infection after a surgical procedure
  3. treatment of strep throat caused by culture identified Streptococcus pyogenes
  4. empiric therapy of pneumonia while waiting for culture results

Which of the following terms refers to the ability of an antimicrobial drug to harm the target microbe without harming the host?

  1. mode of action
  2. therapeutic level
  3. spectrum of activity
  4. selective toxicity

Which of the following is not a type of β-lactam antimicrobial?

Which of the following does not bind to the 50S ribosomal subunit?

Which of the following antimicrobials inhibits the activity of DNA gyrase?

Which of the following is not an appropriate target for antifungal drugs?

Which of the following drug classes specifically inhibits neuronal transmission in helminths?

Which of the following is a nucleoside analog commonly used as a reverse transcriptase inhibitor in the treatment of HIV?

Which of the following is an antimalarial drug that is thought to increase ROS levels in target cells?

Which of the following resistance mechanisms describes the function of β-lactamase?

Which of the following resistance mechanisms is commonly effective against a wide range of antimicrobials in multiple classes?

  1. efflux pump
  2. target mimicry
  3. target modification
  4. target overproduction

Which of the following resistance mechanisms is the most nonspecific to a particular class of antimicrobials?

Which of the following types of drug-resistant bacteria do not typically persist in individuals as a member of their intestinal microbiota?

In the Kirby-Bauer disk diffusion test, the _______ of the zone of inhibition is measured and used for interpretation.

Which of the following techniques cannot be used to determine the minimum inhibitory concentration of an antimicrobial drug against a particular microbe?

  1. Etest
  2. microbroth dilution test
  3. Kirby-Bauer disk diffusion test
  4. macrobroth dilution test

The utility of an antibiogram is that it shows antimicrobial susceptibility trends

  1. over a large geographic area.
  2. for an individual patient.
  3. in research laboratory strains.
  4. in a localized population.

Which of the following has yielded compounds with the most antimicrobial activity?

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    In nature, some microbes produce substances that inhibit or kill other microbes that might otherwise compete for the same resources. Humans have successfully exploited these abilities, using microbes to mass-produce substances that can be used as antimicrobial drugs (see Figure 10.1). Since their discovery, antimicrobial drugs have saved countless lives, and they remain an essential tool for treating and controlling infectious disease. But their widespread and often unnecessary use has had an unintended side effect: the rise of multidrug-resistant microbial strains. In this chapter, we will discuss how antimicrobial drugs work, why microbes develop resistance, and what health professionals can do to encourage responsible use of antimicrobials.

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    As essential conservative component of the innate immune systems of living organisms, antimicrobial peptides (AMPs) could complement pharmaceuticals that increasingly fail to combat various pathogens exhibiting increased resistance to microbial antibiotics. Among the properties of AMPs that suggest their potential as therapeutic agents, diverse peptides in the venoms of various predators demonstrate antimicrobial activity and kill a wide range of microorganisms. To identify potent AMPs, the study reported here involved a transcriptomic profiling of the tentacle secretion of the sea anemone Cnidopus japonicus. An in silico search algorithm designed to discover toxin-like proteins containing AMPs was developed based on the evaluation of the properties and structural peculiarities of amino acid sequences. The algorithm revealed new proteins of the anemone containing antimicrobial candidate sequences, and 10 AMPs verified using high-throughput proteomics were synthesized. The antimicrobial activity of the candidate molecules was experimentally estimated against Gram-positive and -negative bacteria. Ultimately, three peptides exhibited antimicrobial activity against bacterial strains, which suggests that the method can be applied to reveal new AMPs in the venoms of other predators as well.

    Antibiotics discovered that kill bacteria in a new way

    A new group of antibiotics with a unique approach to attacking bacteria has been discovered, making it a promising clinical candidate in the fight against antimicrobial resistance.

    The newly-found corbomycin and the lesser-known complestatin have a never-before-seen way to kill bacteria, which is achieved by blocking the function of the bacterial cell wall. The discovery comes from a family of antibiotics called glycopeptides that are produced by soil bacteria.

    The researchers also demonstrated in mice that these new antibiotics can block infections caused by the drug resistant Staphylococcus aureus which is a group of bacteria that can cause many serious infections.

    The findings were published in Nature today.

    "Bacteria have a wall around the outside of their cells that gives them shape and is a source of strength," said study first author Beth Culp, a PhD candidate in biochemistry and biomedical sciences at McMaster.

    "Antibiotics like penicillin kill bacteria by preventing building of the wall, but the antibiotics that we found actually work by doing the opposite -- they prevent the wall from being broken down. This is critical for cell to divide.

    "In order for a cell to grow, it has to divide and expand. If you completely block the breakdown of the wall, it is like it is trapped in a prison, and can't expand or grow."

    Looking at the family tree of known members of the glycopeptides, researchers studied the genes of those lacking known resistance mechanisms, with the idea they might be an antibiotic demonstrating a different way to attack bacteria.

    "We hypothesized that if the genes that made these antibiotics were different, maybe the way they killed the bacteria was also different," said Culp.

    The group confirmed that the bacterial wall was the site of action of these new antibiotics using cell imaging techniques in collaboration with Yves Brun and his team from the Université de Montréal.

    Culp said: "This approach can be applied to other antibiotics and help us discover new ones with different mechanisms of action. We found one completely new antibiotic in this study, but since then, we've found a few others in the same family that have this same new mechanism."

    The team is led by professor Gerry Wright of the David Braley Centre for Antibiotic Discovery within the Michael G. DeGroote Institute for Infectious Disease Research at McMaster.

    The research was funded by the Canadian Institutes of Health Research and the Ontario Research Fund.

    How Do Antibiotics Work?

    Before the 20th century, there were no effective treatments for infections caused by bacteria, including pneumonia, tuberculosis, gonorrhea, rheumatic fever and urinary tract infections. But in 1929, bacteriologist Alexander Fleming discovered the first true antibiotic, penicillin, ushering in a new age of medicine.

    Since then, scientists have found dozens of antibiotics, which fight bacteria in a variety of ways.

    Many antibiotics, including penicillin, work by attacking the cell wall of bacteria. Specifically, the drugs prevent the bacteria from synthesizing a molecule in the cell wall called peptidoglycan, which provides the wall with the strength it needs to survive in the human body.

    But there are multiple ways to inhibit the assembly of peptidoglycan &mdash vancomycin, for example, also interferes with peptidoglycan, but not in the same way that penicillin does.

    Other antibiotics prevent successful DNA replication in bacteria. A class of antimicrobials called quinolones targets DNA gyrase, an important enzyme that helps unwind DNA for replication. By removing gyrase from the equation, ciprofloxacin and similar antibiotics effectively prevent the bacteria from multiplying.

    Some antibiotics, including tetracycline, which is used to treat acne, respiratory tract infections and other conditions, inhibit protein synthesis. The drugs do this by preventing key molecules from binding to selected sites on cell structures called ribosomes, where protein synthesis occurs. Without its proteins, the bacteria can't carry out vital functions, including asexual reproduction.

    Rifamycin, a group of tuberculosis-fighting antibiotics, achieves a similar effect by inhibiting the synthesis of RNA, a molecule involved in translating the body's DNA into proteins.

    Still other antibiotics fight infections by stopping bacteria from producing folic acid &mdash an essential vitamin &mdash or disputing the structure of a bacterium's cell membrane, which controls how substances move in and out of the cell.


    The inherent instability of peptides toward metabolic degradation is an obstacle on the way toward bringing potential peptide drugs onto the market. Truncation can be one way to increase the proteolytic stability of peptides, and in the present study the susceptibility against trypsin, which is one of the major proteolytic enzymes in the gastrointestinal tract, was investigated for several short and diverse libraries of promising cationic antimicrobial tripeptides. Quite surprisingly, trypsin was able to cleave very small cationic antimicrobial peptides at a substantial rate. Isothermal titration calorimetry studies revealed stoichiometric interactions between selected peptides and trypsin, with dissociation constants ranging from 1 to 20 µM. Introduction of hydrophobic C-terminal amide modifications and likewise bulky synthetic side chains on the central amino acid offered an effective way to increased half-life in our assays. Analysis of the degradation products revealed that the location of cleavage changed when different end-capping strategies were employed to increase the stability and the antimicrobial potency. This suggests that trypsin prefers a bulky hydrophobic element in S1′ in addition to a positively charged side chain in S1 and that this binding dictates the mode of cleavage for these substrates. Molecular modeling studies supported this hypothesis, and it is shown that small alterations of the tripeptide result in two very different modes of trypsin binding and degradation. The data presented allows for the design of stable cationic antibacterial peptides and/or peptidomimetics based on several novel design principles.

    Watch the video: Αντιβιοτικά Ευρωπαϊκή ημέρα για τα αντιβιοτικά -18 Νοεμβρίου (May 2022).


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