antibacterial (Book) Flashcards by EDGAR JORDAN ESPINOLA

discovered the antibacterial properties of penicillin, which later led to the modern antibiotic era.

(1929): Sir Alexander Fleming

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medical miracles

antibiotics, along with immunizations

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overuse has led to resistant organisms, some untreatable by common antibiotics

Antibiotic resistance

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introduced penicillin into therapy, making it a practical medical treatment.

Florey and Chain (1938)

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observed that anthrax bacilli were killed when grown with certain bacteria, leading Vuillemin to define antibiosis (survival of the fittest).

(1877): Pasteur and Joubert

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Origin of the Term “Antibiotic”: Derived from antibiosis, meaning

against life.

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Antibiotics are substances produced by microorganisms that inhibit or destroy other microorganisms.

Waksman’s Definition (1942)

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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.

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isolated the antibacterial antibiotic tyrocidin from Bacillus brevis, suggesting the presence of many natural antibiotic substances.

Dubois

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Waksman and his team isolated streptomycin from

Streptomyces griseus, marking a major breakthrough.

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It was the first antibiotic effective against Mycobacterium tuberculosis and Gram-negative bacteria, proving soil microorganisms to be a valuable antibiotic source.

Streptomycin

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Broad-spectrum antibacterial antibiotics:

Chloramphenicol, tetracyclines.

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Antifungal antibiotics:

Nystatin, griseofulvin.

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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.

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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).

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Drugs like chloramphenicol and tetracyclines can inhibit a wide range of pathogens.

Broad-Spectrum Antibiotics:

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Clinical Relevance: The designation of an antibiotic as “broad-spectrum” is only meaningful if

it is clinically effective against specific microorganisms.

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Limitations: Some antibiotics included in the broad-spectrum category may only be effective at

high concentrations against certain microbes.

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High selective toxicity (e.g., penicillins, cycloserine).

Inhibition of Cell Wall Synthesis

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Some antibiotics mimic essential bacterial metabolites (cycloserine mimics D-alanine).

Competitive Antagonism

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antibiotics selectively interfere with microbial protein synthesis (e.g., aminoglycosides,
tetracyclines,
macrolides,
chloramphenicol,
lincomycin).

Inhibition of Protein Synthesis

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interfere with nucleic acid synthesis.(e.g., rifampin).

Inhibition of Nucleic Acid Synthesis

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interfere with microbial cell membrane integrity and function.
(e.g., polymyxins, polyenes).

Disruption of Cell Membranes

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are the most successful anti-infective agents

Antibiotics that interfere with the metabolic systems found in microorganisms and not in mammalian cells

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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:

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

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

antibacterial (Book) Flashcards

(100 cards)