Antibiotics lect 17
Case Studies: Antibacterials
Introduction
These lectures focus on case studies, particularly antibacterials.
The primary goal is to understand the principles of drug design rather than memorizing specific examples.
Antibiotics target bacteria (antibacterial compounds), while antimicrobials target bacteria, fungi, and other microorganisms.
Microorganisms can cause various infections in the brain (meningitis), lungs (tuberculosis), skin, and other areas.
History of Antibiotics
Early civilizations knew some mixtures helped with infections but lacked understanding of the mechanisms.
1670s: Bacteria were observed following the invention of microscopy.
Louis Pasteur: Demonstrated that sterilizing water prevented microorganism growth, leading to pasteurization.
Joseph Lister: Introduced sterilization of equipment and wounds using carbolic acid (phenol) to reduce complications and deaths in surgery during the 1860s.
Key Discoveries
1910: Paul Ehrlich developed arsphenamine for heartworm bacterial infection and coined the term "magic bullet," referring to a compound with no side effects, selectively targeting the disease.
1928: Fleming discovered penicillin.
Shortly after: Sulfonamides were discovered.
1940s-1960s: A wide range of antimicrobial compounds were discovered, forming the basis for many antibiotics used today.
Initial optimism about conquering all diseases was tempered by the rapid evolution of bacteria.
Antimicrobial Resistance
The World Health Organization identifies antimicrobial resistance as a major threat to humanity.
The development of new antimicrobial compounds is not financially attractive for companies due to the rapid development of resistance and potential use as a last-resort antibiotic.
Similar issues exist for neglected diseases affecting populations without financial means.
Research in antibacterial compounds continues in academia and other sectors.
Targeting Bacteria
Antibacterial development focuses on the differences between bacterial and animal cells.
Animal cells contain organelles and a nucleus, while bacterial cells lack a nucleus.
Bacterial cells have a cell wall in addition to a cell membrane, unlike animal cells.
Bacterial cells are self-sufficient, producing their required compounds, leading to differences in internal biochemistry that can be targeted.
Gram-Positive and Gram-Negative Bacteria
Gram-positive bacteria have a thick outer wall that retains dye during Gram staining.
Gram-negative bacteria have two membranes with a periplasmic space in between, and the dye washes out during Gram staining.
Both types have lipopolysaccharides and molecular recognition sites on the outside.
Mechanisms for Interfering with Bacteria
Targeting bacterial enzymes (e.g., sulfonamides).
Targeting cell wall synthesis (e.g., penicillins, peptides).
Targeting interactions with plasma membranes (e.g., polymyxins).
Targeting inner biochemistry, such as protein synthesis (e.g., tetracyclines, chloramphenicol).
Targeting transcription of nucleic acids (e.g., proflavine).
Sulfonamides
Discovered accidentally when prontosil, a dye, showed antibacterial properties.
Prontosil is a prodrug, metabolized into the active compound sulfonilamide inside the microorganism.
The active compound requires a free group. The R group must be hydrogen.
Effective sulfonamides usually have aromatic or heteroaromatic groups attached to the nitrogen.
Mechanism of Action for Sulfonamides
Bacteria synthesize tetrahydrofolate (folic acid), a cofactor, using para-aminobenzoic acid (PABA).
Sulfonamides interfere with this process by mimicking PABA and inhibiting the enzyme involved.
Resistance develops when bacteria produce more PABA, overwhelming the sulfonamide.
Sulfonamides are bioisosteres of carboxylic acids, leading to their interaction with the enzyme's active site.
If you look at these two compounds, the inhibitor, and the active agent, you will see what we talked about a couple of weeks back of bioisosteres. So this moiety here, the sulfonamide is the bioisostere for the carboxylic acid. If you do some studies to look at the active site, you will see that there's binding sites here, and there are binding sites across here of on the negative charge of the carboxyclic acid from an actual substrate.
Penicillins
Penicillin was discovered by Alexander Fleming when airborne fungus spores contaminated his cultures.
The structure was elucidated by Dorothy Hodgkin.
Penicillins have a four-membered beta-lactam ring and a thiazolidine ring.
Penicillins inhibit cell wall synthesis in bacteria.
Bacterial Cell Wall Synthesis
The bacterial cell wall contains N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) units.
Short chains of amino acids, including alanine, isoglutamate, lysine, and two D-alanines, extend from NAM.
Strands of amino acids come off of the aminoglycosides backbone. Coming off of that we have some strands of amino acids. Then off the Lysine residues we grow four strands of glycines. These bonds bond to another Lysine residue on neighboring strands.
Peptidoglycans are cross-linked to create a strong, rigid cell wall.
The knitting process is done by an enzyme which recognizes deaminine alanine residues and kicks one of the alanines out. It then grabs hold of the four glycine residues and pushes it together with the alanine to do the lipid process; recognizes the diallo dialla, attaches itself to it, and the alanines gets kicked out. Then it grabs hold of the end of that and forms a bond there, and then the enzymes are released and go off to do the work again.
Cross-linking is performed by an enzyme that recognizes two D-alanine residues, removes one, and links the remaining alanine to a glycine residue.
The cross-linking process requires an enzyme recognizes the di-alanine residues.
Penicillin Mechanism of Action
Penicillins contain a beta-lactam ring (cyclic amide) fused to a thiazolidine ring (five-membered ring with sulfur and nitrogen).
Variations in the acyl side chain lead to different penicillin analogs.
Penicillin mimics the di-alanine structure, leading to recognition by the enzyme involved in cell wall synthesis.
The serine residue of the enzyme attacks the amide bond, forming a covalent bond that is displaced by the four lysine units. In summary, we met sulfonamides, which target the folic acid mechanism. We have met pencillins, which inhibits the peptidoglycan synthesis.
Penicillin Summary
Sulfonamides target folic acid metabolism.
Penicillin inhibits peptidoglycan synthesis thus cell wall biosynthesis.
Introduction
These lectures focus on case studies of antibacterials to understand drug design principles.
The goal is to grasp the fundamental principles of drug design rather than memorizing specific examples.
Antibiotics are specifically designed to target bacteria. Antimicrobials, on the other hand, have a broader spectrum and target bacteria, fungi, and other microorganisms.
Microorganisms can cause infections in various body areas such as the brain (meningitis), lungs (tuberculosis), and skin.
History of Antibiotics
Early civilizations utilized mixtures with some efficacy against infections, though without understanding the underlying mechanisms.
1670s: The advent of microscopy enabled the observation of bacteria.
Louis Pasteur: Demonstrated that sterilizing water effectively prevented microorganism growth, which led to the development of pasteurization.
Joseph Lister: Pioneered the sterilization of equipment and wounds using carbolic acid (phenol) to decrease complications and mortality rates during surgery in the 1860s.
Key Discoveries
1910: Paul Ehrlich synthesized arsphenamine to combat heartworm bacterial infection. He also coined the term "magic bullet," which refers to a compound capable of selectively targeting a disease without causing side effects.
1928: Alexander Fleming made the accidental yet groundbreaking discovery of penicillin.
Shortly After: Sulfonamides were discovered and recognized for their antibacterial properties.
1940s-1960s: This period saw the discovery of numerous antimicrobial compounds, laying the groundwork for many of the antibiotics still in use today.
Initial high hopes for eradicating all diseases were soon met with the challenge of rapid bacterial evolution and the development of resistance.
Antimicrobial Resistance
The World Health Organization (WHO) recognizes antimicrobial resistance as a significant global threat to human health.
The development of new antimicrobial compounds faces financial disincentives for pharmaceutical companies due to the swift emergence of resistance and their potential designation as last-resort antibiotics.
Similar challenges exist in addressing neglected diseases that affect populations lacking financial resources.
Research into antibacterial compounds persists within academic institutions and other sectors.
Targeting Bacteria
Antibacterial development leverages the differences between bacterial and animal cells.
Animal cells are characterized by organelles and a nucleus, whereas bacterial cells lack a nucleus.
Bacterial cells possess a cell wall in addition to a cell membrane, a feature absent in animal cells.
Bacterial cells are self-sufficient, synthesizing all necessary compounds internally. This independence leads to variances in internal biochemistry that can be exploited for targeted intervention.
Gram-Positive and Gram-Negative Bacteria
Gram-positive bacteria have a thick outer cell wall composed of peptidoglycan, which retains the dye during Gram staining, causing them to appear purple under a microscope.
Gram-negative bacteria feature a more complex structure with two membranes separated by a periplasmic space. Their thinner peptidoglycan layer does not retain the dye as effectively, causing them to appear pink or red after Gram staining.
Both types of bacteria have lipopolysaccharides (LPS) and molecular recognition sites on their outer surfaces, which play crucial roles in bacterial identification and immune response.
Mechanisms for Interfering with Bacteria
Targeting bacterial enzymes (e.g., sulfonamides).
Targeting cell wall synthesis (e.g., penicillins, peptides).
Targeting interactions with plasma membranes (e.g., polymyxins).
Targeting inner biochemistry, such as protein synthesis (e.g., tetracyclines, chloramphenicol).
Targeting transcription of nucleic acids (e.g., proflavine).
Sulfonamides
Sulfonamides were discovered serendipitously when prontosil, a dye, exhibited antibacterial activity in vivo.
Prontosil functions as a prodrug. It requires metabolism into the active compound, sulfonilamide, within the microorganism to exert its antibacterial effects.
The active compound necessitates a free group. The R group must be hydrogen for activity.
Effective sulfonamides typically feature aromatic or heteroaromatic groups attached to the nitrogen, which enhances their interaction with the target enzyme.
Mechanism of Action for Sulfonamides
Bacteria synthesize tetrahydrofolate (folic acid), an essential cofactor involved in various metabolic processes, using para-aminobenzoic acid (PABA) as a precursor.
Sulfonamides act as competitive inhibitors by mimicking PABA, thereby disrupting the enzymatic steps required for tetrahydrofolate synthesis.
Resistance to sulfonamides can emerge when bacteria increase the production of PABA, effectively outcompeting the sulfonamide for binding to the enzyme's active site.
Sulfonamides are bioisosteres of carboxylic acids, which enables them to interact with the enzyme's active site. They bind to the same region as PABA but disrupt the normal enzymatic process.
Bioisosteres: Sulfonamides mimic the structure of carboxylic acids to bind to the active site.
Penicillins
Penicillin was discovered by Alexander Fleming in 1928 after airborne spores of Penicillium mold contaminated his bacterial cultures.
The structure of penicillin was elucidated by Dorothy Hodgkin, who used X-ray crystallography to determine its complex molecular arrangement.
Penicillins are characterized by a four-membered beta-lactam ring and a thiazolidine ring. These structural elements are crucial for their mechanism of action.
Penicillins inhibit bacterial cell wall synthesis by targeting enzymes responsible for peptidoglycan cross-linking.
Bacterial Cell Wall Synthesis
The bacterial cell wall is composed of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) units. These sugars form the backbone of peptidoglycan strands.
Short chains of amino acids, including alanine, isoglutamate, lysine, and two D-alanines, extend from NAM. These amino acids are crucial for cross-linking between peptidoglycan strands.
Strands of amino acids come off of the aminoglycosides backbone. Coming off of that we have some strands of amino acids. Then off the Lysine residues we grow four strands of glycines. These bonds bond to another Lysine residue on neighboring strands.
Peptidoglycans are cross-linked to create a strong, rigid cell wall.The extensive cross-linking provides structural integrity to the bacterial cell wall, protecting it from osmotic pressure and mechanical stress.
The knitting process is done by an enzyme which recognizes deaminine alanine residues and kicks one of the alanines out. It then grabs hold of the four glycine residues and pushes it together with the alanine to do the lipid process; recognizes the diallo dialla, attaches itself to it, and the alanines gets kicked out. Then it grabs hold of the end of that and forms a bond there, and then the enzymes are released and go off to do the work again.
Cross-linking is performed by an enzyme that recognizes two D-alanine residues, removes one, and links the remaining alanine to a glycine residue. This process is essential for the formation of the peptidoglycan layer.
The cross-linking process requires an enzyme recognizes the di-alanine residues.
Penicillin Mechanism of Action
Penicillins contain a beta-lactam ring (cyclic amide) fused to a thiazolidine ring (five-membered ring with sulfur and nitrogen).
Variations in the acyl side chain lead to different penicillin analogs. The specific structure of the side chain influences the drug's pharmacokinetic and pharmacodynamic properties.
Penicillin mimics the di-alanine structure, leading to recognition by the enzyme involved in cell wall synthesis. This mimicry allows penicillin to bind to the active site of the transpeptidase enzyme.
The serine residue of the enzyme attacks the amide bond, forming a covalent bond that is displaced by the four lysine units. In summary, we met sulfonamides, which target the folic acid mechanism. We have met pencillins, which inhibits the peptidoglycan synthesis.
Penicillin Summary
Sulf
Introduction
These lectures focus on case studies of antibacterials to understand drug design principles.
The goal is to grasp the fundamental principles of drug design rather than memorizing specific examples.
Antibiotics are specifically designed to target bacteria. Antimicrobials, on the other hand, have a broader spectrum and target bacteria, fungi, and other microorganisms.
Microorganisms can cause infections in various body areas such as the brain (meningitis), lungs (tuberculosis), and skin.
History of Antibiotics
Early civilizations utilized mixtures with some efficacy against infections, though without understanding the underlying mechanisms.
1670s: The advent of microscopy enabled the observation of bacteria.
Louis Pasteur: Demonstrated that sterilizing water effectively prevented microorganism growth, which led to the development of pasteurization.
Joseph Lister: Pioneered the sterilization of equipment and wounds using carbolic acid (phenol) to decrease complications and mortality rates during surgery in the 1860s.
Key Discoveries
1910: Paul Ehrlich synthesized arsphenamine to combat heartworm bacterial infection. He also coined the term "magic bullet," which refers to a compound capable of selectively targeting a disease without causing side effects.
1928: Alexander Fleming made the accidental yet groundbreaking discovery of penicillin.
Shortly After: Sulfonamides were discovered and recognized for their antibacterial properties.
1940s-1960s: This period saw the discovery of numerous antimicrobial compounds, laying the groundwork for many of the antibiotics still in use today.
Initial high hopes for eradicating all diseases were soon met with the challenge of rapid bacterial evolution and the development of resistance.
Antimicrobial Resistance
The World Health Organization (WHO) recognizes antimicrobial resistance as a significant global threat to human health.
The development of new antimicrobial compounds faces financial disincentives for pharmaceutical companies due to the swift emergence of resistance and their potential designation as last-resort antibiotics.
Similar challenges exist in addressing neglected diseases that affect populations lacking financial resources.
Research into antibacterial compounds persists within academic institutions and other sectors.
Targeting Bacteria
Antibacterial development leverages the differences between bacterial and animal cells.
Animal cells are characterized by organelles and a nucleus, whereas bacterial cells lack a nucleus.
Bacterial cells possess a cell wall in addition to a cell membrane, a feature absent in animal cells.
Bacterial cells are self-sufficient, synthesizing all necessary compounds internally. This independence leads to variances in internal biochemistry that can be exploited for targeted intervention.
Gram-Positive and Gram-Negative Bacteria
Gram-positive bacteria have a thick outer cell wall composed of peptidoglycan, which retains the dye during Gram staining, causing them to appear purple under a microscope.
Gram-negative bacteria feature a more complex structure with two membranes separated by a periplasmic space. Their thinner peptidoglycan layer does not retain the dye as effectively, causing them to appear pink or red after Gram staining.
Both types of bacteria have lipopolysaccharides (LPS) and molecular recognition sites on their outer surfaces, which play crucial roles in bacterial identification and immune response.
Mechanisms for Interfering with Bacteria
Targeting bacterial enzymes (e.g., sulfonamides).
Targeting cell wall synthesis (e.g., penicillins, peptides).
Targeting interactions with plasma membranes (e.g., polymyxins).
Targeting inner biochemistry, such as protein synthesis (e.g., tetracyclines, chloramphenicol).
Targeting transcription of nucleic acids (e.g., proflavine).
Sulfonamides
Sulfonamides were discovered serendipitously when prontosil, a dye, exhibited antibacterial activity in vivo.
Prontosil functions as a prodrug. It requires metabolism into the active compound, sulfonilamide, within the microorganism to exert its antibacterial effects.
The active compound necessitates a free group. The R group must be hydrogen for activity.
Effective sulfonamides typically feature aromatic or heteroaromatic groups attached to the nitrogen, which enhances their interaction with the target enzyme.
Mechanism of Action for Sulfonamides
Bacteria synthesize tetrahydrofolate (folic acid), an essential cofactor involved in various metabolic processes, using para-aminobenzoic acid (PABA) as a precursor.
Sulfonamides act as competitive inhibitors by mimicking PABA, thereby disrupting the enzymatic steps required for tetrahydrofolate synthesis.
Resistance to sulfonamides can emerge when bacteria increase the production of PABA, effectively outcompeting the sulfonamide for binding to the enzyme's active site.
Sulfonamides are bioisosteres of carboxylic acids, which enables them to interact with the enzyme's active site. They bind to the same region as PABA but disrupt the normal enzymatic process.
Bioisosteres: Sulfonamides mimic the structure of carboxylic acids to bind to the active site.
Penicillins
Penicillin was discovered by Alexander Fleming in 1928 after airborne spores of Penicillium mold contaminated his bacterial cultures.
The structure of penicillin was elucidated by Dorothy Hodgkin, who used X-ray crystallography to determine its complex molecular arrangement.
Penicillins are characterized by a four-membered beta-lactam ring and a thiazolidine ring. These structural elements are crucial for their mechanism of action.
Penicillins inhibit bacterial cell wall synthesis by targeting enzymes responsible for peptidoglycan cross-linking.
Bacterial Cell Wall Synthesis
The bacterial cell wall is composed of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) units. These sugars form the backbone of peptidoglycan strands.
Short chains of amino acids, including alanine, isoglutamate, lysine, and two D-alanines, extend from NAM. These amino acids are crucial for cross-linking between peptidoglycan strands.
Strands of amino acids come off of the aminoglycosides backbone. Coming off of that we have some strands of amino acids. Then off the Lysine residues we grow four strands of glycines. These bonds bond to another Lysine residue on neighboring strands.
Peptidoglycans are cross-linked to create a strong, rigid cell wall.The extensive cross-linking provides structural integrity to the bacterial cell wall, protecting it from osmotic pressure and mechanical stress.
The knitting process is done by an enzyme which recognizes deaminine alanine residues and kicks one of the alanines out. It then grabs hold of the four glycine residues and pushes it together with the alanine to do the lipid process; recognizes the diallo dialla, attaches itself to it, and the alanines gets kicked out. Then it grabs hold of the end of that and forms a bond there, and then the enzymes are released and go off to do the work again.
Cross-linking is performed by an enzyme that recognizes two D-alanine residues, removes one, and links the remaining alanine to a glycine residue. This process is essential for the formation of the peptidoglycan layer.
The cross-linking process requires an enzyme recognizes the di-alanine residues.
Penicillin Mechanism of Action
Penicillins contain a beta-lactam ring (cyclic amide) fused to a thiazolidine ring (five-membered ring with sulfur and nitrogen).
Variations in the acyl side chain lead to different penicillin analogs. The specific structure of the side chain influences the drug's pharmacokinetic and pharmacodynamic properties.
Penicillin mimics the di-alanine structure, leading to recognition by the enzyme involved in cell wall synthesis. This mimicry allows penicillin to bind to the active site of the transpeptidase enzyme.
The serine residue of the enzyme attacks the amide bond, forming a covalent bond that is displaced by the four lysine units. In summary, we met sulfonamides, which target the folic acid mechanism. We have met pencillins, which inhibits the peptidoglycan synthesis.
Penicillin Summary
Sulf