antibacterial (Book) Flashcards
discovered the antibacterial properties of penicillin, which later led to the modern antibiotic era.
(1929): Sir Alexander Fleming
medical miracles
antibiotics, along with immunizations
overuse has led to resistant organisms, some untreatable by common antibiotics
Antibiotic resistance
introduced penicillin into therapy, making it a practical medical treatment.
Florey and Chain (1938)
observed that anthrax bacilli were killed when grown with certain bacteria, leading Vuillemin to define antibiosis (survival of the fittest).
(1877): Pasteur and Joubert
Origin of the Term “Antibiotic”: Derived from antibiosis, meaning
against life.
Antibiotics are substances produced by microorganisms that inhibit or destroy other microorganisms.
Waksman’s Definition (1942)
Criteria for a Substance to be Classified as an Antibiotic:
- It is a product of metabolism (although it may be duplicated or even have been anticipated by chemical synthesis).
- It is a synthetic product produced as a structural analog of a naturally occurring antibiotic.
- It antagonizes the growth or survival of one or more species of microorganisms.
- It is effective in low concentrations.
isolated the antibacterial antibiotic tyrocidin from Bacillus brevis, suggesting the presence of many natural antibiotic substances.
Dubois
Waksman and his team isolated streptomycin from
Streptomyces griseus, marking a major breakthrough.
It was the first antibiotic effective against Mycobacterium tuberculosis and Gram-negative bacteria, proving soil microorganisms to be a valuable antibiotic source.
Streptomycin
Broad-spectrum antibacterial antibiotics:
Chloramphenicol, tetracyclines.
Antifungal antibiotics:
Nystatin, griseofulvin.
Challenges in Medical Use: Only a few antibiotics are widely used because they must meet several criteria:
Selective Toxicity: Effective against pathogens or cancer cells while minimizing harm to the host.
Chemical Stability: Must remain potent during storage and processing.
Pharmacokinetics: Should allow convenient dosing while being eliminated efficiently.
Commercial Production of Antibiotics
The production process generally follows six steps:
Preparation of Pure Culture – A pure strain of the antibiotic-producing organism is grown.
Fermentation – The organism is cultured in a controlled medium to produce the antibiotic.
Isolation – The antibiotic is extracted from the fermentation broth.
Purification – The extracted antibiotic is refined to remove impurities.
Assay – The product undergoes assays for potency, sterility, and absence of pyrogens (fever-causing substances).
Formulation – The purified antibiotic is converted into stable dosage forms (e.g., tablets, capsules, injections).
Drugs like chloramphenicol and tetracyclines can inhibit a wide range of pathogens.
Broad-Spectrum Antibiotics:
Clinical Relevance: The designation of an antibiotic as “broad-spectrum” is only meaningful if
it is clinically effective against specific microorganisms.
Limitations: Some antibiotics included in the broad-spectrum category may only be effective at
high concentrations against certain microbes.
High selective toxicity (e.g., penicillins, cycloserine).
Inhibition of Cell Wall Synthesis
Some antibiotics mimic essential bacterial metabolites (cycloserine mimics D-alanine).
Competitive Antagonism
antibiotics selectively interfere with microbial protein synthesis (e.g., aminoglycosides,
tetracyclines,
macrolides,
chloramphenicol,
lincomycin).
Inhibition of Protein Synthesis
interfere with nucleic acid synthesis.(e.g., rifampin).
Inhibition of Nucleic Acid Synthesis
interfere with microbial cell membrane integrity and function.
(e.g., polymyxins, polyenes).
Disruption of Cell Membranes
are the most successful anti-infective agents
Antibiotics that interfere with the metabolic systems found in microorganisms and not in mammalian cells
antibiotic is bactericidal
crucial for serious, life-threatening infections when the host’s natural defenses are deficient.
(kills bacteria)
bacteriostatic
(inhibits growth).
Several important antibiotics share a macrolide structure, including erythromycin and oleandomycin.
(large lactone ring)
Comprises a group of compounds that are very closely related chemically.
Tetracycline Family
compounds contain closely related amino sugar moieties, such as those found in streptomycins, kanamycins, neomycins, paromomycins, and gentamicins.
Aminoglycosides:
Nystatin and amphotericins are examples
conjugated polyene compounds.
Bacitracins, tyrothricin, and polymyxins belong to a large group of _________ that exhibit antibiotic action.
Polypeptide Antibiotics
Penicillins and cephalosporins
derived from amino acids.
β-Lactam Antibiotics
pathogens have varied and intricate biological functions,
making multiple inhibition strategies possible.
Different microorganisms produce chemically distinct antibiotics that can
target the same pathogen through different mechanisms
When pathogens develop resistance to one antibiotic
another with a different mechanism of action can still be effective.
can inactivate penicillins and cephalosporins, leading to the development of semisynthetic analogs that resist microbial biotransformation.
β-lactamase–producing bacteria
(e.g., Staphylococcus, Pseudomonas, Klebsiella, E. coli) are often resistant to multiple antibiotics, posing serious medical challenges.
Nosocomial Infections: Hospital-acquired infections
The improper use of antibiotics has contributed to the
emergence of resistant strains.
The dominant class antibiotics with a four-membered cyclic amide are the most widely used for bacterial infections.
β-Lactam Antibiotics:
β-Lactam Antibiotics:
Penicillins:
Cephalosporins:
Semisynthetic β-Lactams:
the first antibiotic used in therapy
Penicillin G (benzylpenicillin)
a close biosynthetic relative of benzylpenicillin
Penicillin V (phenoxymethyl penicillin)
These remain the agents of choice for treating Gram-positive bacterial infections
Penicillins:
A second major group of β-lactam antibiotics.
Cephalosporins:
Chemical modifications of penicillins and cephalosporins
effective against penicillin-resistant bacteria (e.g., penicillinase-producing staphylococci)
Can target Gram-negative bacilli
Semisynthetic β-Lactams
Apart from a few strains with inherent or acquired resistance, almost all bacterial species are susceptible to at least
one β-lactam antibiotic.
β-Lactam Antibiotics: Key Properties
Broad-spectrum antibacterial action
Potent and rapid bactericidal effect against growing bacteria
Low toxicity and minimal adverse effects in the host
Mechanism of Action: β-Lactam Antibiotics
Inhibition of Bacterial Cell Wall Synthesis
Selectively inhibits peptidoglycan biosynthesis, weakening the bacterial cell wall
Penicillins and cephalosporins acylate D-transpeptidase, preventing peptide cross-link formation
Also inhibits D-alanine carboxypeptidases, disrupting cell wall integrity
(PBPs)
Penicillin-Binding Proteins
PBP 1a & 1b
Transpeptidases involved in cell elongation
Inhibition → Spheroplast formation & rapid cell lysis
PBP 2
Maintains rod shape of bacilli
Inhibition → Ovoid or round bacterial forms
PBP 3
Required for septum formation (cell division)
Inhibition → Filamentous, non-separating bacterial cells
PBPs 4-6
Carboxypeptidases that cleave D-alanine bonds
Inhibition is not lethal but affects cross-linking
Preferentially binds PBP 3
Penicillin G
Higher affinity for PBP 1a
Higher affinity for PBP 1a
Binds only to PBP 2, unlike most β-lactams that target PBPs 1, 2, and 3
Amdinocillin
Initially, was thought to be a single substance, with variations in activity attributed to inert materials in different samples.
penicillin
Penicillins are a group of compounds, differing in_______________.
These variations affect antibiotic potency, stability, and physicochemical properties.
the amide side chain’s acid moiety.
Modern production of penicillin relies on
Penicillium notatum and Penicillium chrysogenum
1 USP unit =
0.6 µg of penicillin G sodium.
Biosynthetic Origin of 6-Aminopenicillanic Acid (6-APA):
Derived from two amino acids:
L-Cysteine: Provides sulfur (S-1), C-5, C-6, C-7, and 6-amino group.
L-Valine: Contributes 2,2-dimethyl, C-2, C-3, N-4, and 3-carboxyl group.
The unusual nature of the β-lactam ring delayed the elucidation of penicillin’s structure.
Fused β-lactam-thiazolidine ring structure
Adapted peptide synthesis techniques to produce penicillin V, but with only 10-12% yield.
Sheehan and Henery-Logan’s synthesis
discovered 6-aminopenicillanic acid (6-APA) in P. chrysogenum, allowing new penicillins to be made by
acylation of the 6-amino group.
Developed a process to modify penicillin G potassium, enabling the attachment of new side chains to create
biologically active penicillins
Development of new penicillins: The first commercial products included
phenoxyethylpenicillin (phenethicillin) and dimethoxyphenylpenicillin (methicillin), leading to improved activity and stability
Initially a yellow-to-brown unstable powder requiring refrigeration.
Improved purification led to white crystalline penicillin, which remains stable when dry.
Penicillin allergy
may result from penicilloyl proteins formed in vivo
Gram-negative bacilli are inherently resistant to
penicillins
Some sensitive species can develop resistance through
mutation or natural selection
β-Lactamases hydrolyze the β-lactam ring
inactivating penicillins by converting them into penicilloic acids.
Types of β-lactamase production
Chromosomal or plasmid (R factor) control.
Constitutive (always produced) or inducible (triggered by antibiotics).
hydrolyze the acyl-amino side chain of penicillins.
Found in some Gram-negative bacteria.
Used commercially to prepare 6-APA, a precursor for semisynthetic penicillins.
6-APA is less active and rapidly hydrolyzed.
Acylases
Gram-negative bacteria have a complex outer membrane, which acts as
a barrier to hydrophobic antibiotics.
allow small hydrophilic molecules to pass through the outer membrane.
Porins
Changes in porin number or structure can
educe antibiotic entry and contribute to resistance.
Resistance can result from mutations that decrease PBPs’ affinity for penicillins.
Penicillin-resistant Neisseria gonorrhoeae (non-β-lactamase-producing strains).
Methicillin-resistant Staphylococcus aureus (MRSA).
Some bacteria remain susceptible to growth inhibition but
resist lysis by penicillins.
Due to impaired autolysin activity
preventing cell wall breakdown and bacterial death
Five-membered ring heterocyclic derivatives require bulkier substituents (e.g., 3-aryl and 5-methyl) for effective β-lactamase resistance.
(e.g., oxacillin, cloxacillin, dicloxacillin)
Adding an ionized or polar group at the α-position of the benzyl carbon in penicillin G increases activity against
Gram-negative bacilli.
with an α-amino group) are effective against E. coli, Klebsiella, Haemophilus, Salmonella, Shigella, and non-indole-producing Proteus.
Ampicillin and Amoxicillin
Adding an acidic (carboxy) group at the β-benzyl carbon of penicillin G yields __________, which is effective against Gram-negative bacilli and extends the spectrum to ampicillin-resistant organisms, including Pseudomonas, Klebsiella, and Proteus species.
carbenicillin
The acylamino side chain of penicillins significantly affects their
binding to plasma proteins.
Hydrophobic (lipophilic) groups increase
plasma protein binding.
Polar or ionized groups result in
lower protein binding.
Higher protein binding
may restrict drug availability in tissues, potentially reducing tissue penetration.
Some penicillins are modified to withstand acidic environments (important for oral administration).
Acid-resistant:
Other penicillins may degrade in acidic conditions, thus often requiring parenteral administration.
Non-acid-resistant:
These penicillins (e.g., methicillin, nafcillin) are designed to resist degradation by bacterial β-lactamase enzymes.
Lactamase-resistant
Penicillins that are susceptible to β-lactamase enzymes (e.g., penicillin G).
Lactamase-sensitive
refers to the range of bacteria a penicillin can target, but these categories are relative and may vary in clinical application
spectrum of activity
Targets a limited group of bacteria. Penicillin G is an example, effective mainly against Gram-positive organisms and some Gram-negative cocci.
Narrow-spectrum
A bit broader than narrow-spectrum but not as wide as broad-spectrum. For example, ampicillin
Intermediate-spectrum:
Effective against a wide variety of bacteria, both Gram-positive and Gram-negative. Amoxicillin is a common example.
Broad-spectrum:
Even broader, targeting both Gram-negative and Gram-positive bacteria, often including more resistant strains. Carbenicillin and ticarcillin fall into this category.
Extended-spectrum
Used for infections caused by ampicillin-resistant Gram-negative bacilli.
These drugs don’t offer a distinct advantage over penicillin G or ampicillin in cases where these drugs are effective, and they may even have disadvantages.
Carbenicillin and ticarcillin:
are crucial in treating resistant staph infections but less effective against sensitive organisms.
Penicillinase-resistant penicillins (e.g., methicillin)
has historically been the most commonly used antibiotic for bacterial infections.
It remains the drug of choice for many infections, except in allergic patients.
oral administration ineffective unless combined with antacids
Poorly absorbed from the gastrointestinal (GI) tract
Penicillin G
