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7.3.3: Beta-Lactam Antibiotics- Penicillins and Cephalosporins - Biology

7.3.3:  Beta-Lactam Antibiotics- Penicillins and Cephalosporins - Biology


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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 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. The simplest β-lactam possible is 2-azetidinone.

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).


Allergic reactions to penicillins and cephalosporins: diagnosis, assessment of cross-reactivity and management

Introduction: Beta-lactams (BL) are the main cause of allergic drug reactions mediated by specific immunological mechanisms. Reactions can be IgE or effector T-cell mediated. The new antigenic determinants are recognized by the immunological system in the context of the common beta-lactam structure or the specific differences in the side chains of the antibiotics of this family plus the protein carrier. Areas covered: We have reviewed the recent clinical literature concerning new clinical entities, the progress in diagnosis including the difficulties for in in vivo and or in vitro testing as well as the new algorithms proposed for delabelling subjects classified as allergic to beta-lactams, and recommendations for desensitization procedures. Expert opinion: The knowledge gained over the last years on beta-lactam hypersensitivity has enabled a better understanding and management of cases with allergic reactions to beta-lactams.

Keywords: Allergy cephalosporins cross-reactivity diagnosis management penicillins.


Difference Between Beta Lactam Antibiotics And Macrolides

Antibiotics were thought to be organic compounds produced by microorganisms which are toxic to other microorganisms. An antibiotic was defined as a substance that is produced by one microorganism or of biological origin which at low concentrations can inhibit the growth of, or kill other microorganisms.

The discovery and development of the betalactam antibiotics is the most powerful, important and famous achievement of modern science and technology. Penicillin was the first beta lactam antibiotic that was discovered by an English Bacteriologist, late Sir Alexander Fleming who accidentally discovered the antibiotic Penicillium notatum from a fungus that inhabit soil, which was first reported in 1929. Beta lactam antibiotics are cell wall synthesis inhibitors.

The first antibiotic that belongs to class of macrolide was discovered and isolated in 1952 by J. M. McGuire as a metabolic product of a soil inhabiting fungus Saccharopolyspora erythraea. This fungus was known as Streptomyces erythraeus that belongs to the genus Saccharopolyspora of actinomycete bacteria. Macrolides are protein synthesis inhibitors.

CLASSIFICATION

Antibiotics are generally classified on the basis of theirmolecular structures mode of action and spectrum of activity androute of administration (injectable, oral and topical). Antibiotics that possess same structural class generally shows similar pattern of effectiveness, toxicity and allergic-potential side effects.

Classification of beta lactam antibiotics:

Beta lactam antibiotics are further classified into

Classification of macrolides antibiotics:

CHEMICAL STRUCTURE

Chemical structure of beta lactam antibiotics

Βeta lactam antibiotics are the antibiotic agents that contain a beta-lactam ring in their molecular structure. A beta lactam ring is a four membered lactam (cyclic amide) that contains a 3-carbon and 1-nitrogen which is highly reactive

Chemical structure of macrolides

The general chemical structure of macrolides is characterized by a large lactone ring containing from 12 to 16 atoms to that are attached, through a glycosidic linkage to one or more sugars.

SPECTRUM OF ACTIVITY

Spectrum of Activity of Beta Lactam Antibiotics:

Beta Lactams includes penicillins and cephalosporins, are narrow spectrum antibiotics, which are highly effective against the Gram-positive genera Streptococcus, Gonococcus, and Staphylococcus.

Spectrum of Activity of macrolides:

Macrolides are highly active against gram-positive except enterococci and some gram-negative bacteria. They are also effective against Mycoplasma pneumoniae, Treponema pallidum, Bordetella pertussis, Chlamydia trachomatis, Chlamydophila pneumoniae, Legionella spp., Campylobacter spp.

MECHANISM OF ACTION

Mechanism of Action of Beta Lactam Antibiotics

Beta lactam antibiotic interfere with synthesis of bacterial cell wall, and in the process either kills or inhibits the growth of bacteria. More succinctly, certain bacterial enzymes termed penicillin-binding protein (PBP) are responsible for cross linking peptide units during synthesis of peptidoglycan. Members of beta-lactam antibiotics are able to bind themselves to these PBP enzymes, and in the process, they interfere with the synthesis of peptidoglycan resulting to lysis and cell death.

Mechanism of Action of Macrolides

The mechanism of action of macrolides is inhibition of bacterial protein biosynthesis, they bind to 50S ribosome and inhibit protein synthesis and they are thought to do this by inhibiting peptidyl transferase from adding the growing peptide attached to transfer RNA to the next amino acid as well as inhibiting ribosomal translation.

MECHANISM OF RESISTANCE

Mechanism of Resistance for beta lactam antibiotics

The resistance to beta lactam antibiotic may be caused due to the following reasons


Cephalosporin substrate specificity determinants of TEM-1 beta-lactamase

beta-lactamase is a bacterial enzyme that catalyzes the hydrolysis of beta-lactam antibiotics such as penicillins and cephalosporins. TEM-1 beta-lactamase is a prevalent beta-lactamase found in Gram-negative bacteria and is capable of hydrolyzing both penicillins and cephalosporins, except for the extended-spectrum cephalosporins. To identify the sequence determinants in the active site for a given antibiotic substrate, random libraries were constructed that each contain all possible amino acid combinations for the designated region of TEM-1 beta-lactamase. To establish the determinants of substrate specificity for cephalosporins versus those for penicillins, these active site libraries have been screened for mutants with high levels of activity for the second generation cephalosporin cephaloridine. Based on the sequence results, substitutions of W165S, A237T, and E240C were identified as cephalosporin-specific. Kinetic analysis of these mutants was done to determine whether each is capable of distinguishing between the two classes of antibiotics. Both the A237T and E240C substitutions, alone or in combination, exhibited increased cephalosporinase activity and decreased penicillinase activity relative to the wild-type enzyme. A sequence comparison between functional mutants selected for cephaloridine hydrolytic activity and functional mutants previously selected for ampicillin hydrolytic activity suggests that TEM-1 beta-lactamase has greater restrictions in maintaining cephalosporinase activity versus maintaining penicillinase activity.


Mitochondrial Machineries for Protein Import and Assembly

Nils Wiedemann and Nikolaus Pfanner
Vol. 86, 2017

Abstract

Mitochondria are essential organelles with numerous functions in cellular metabolism and homeostasis. Most of the >1,000 different mitochondrial proteins are synthesized as precursors in the cytosol and are imported into mitochondria by five transport . Read More

Figure 1: Overview of the five major protein import pathways of mitochondria. Presequence-carrying preproteins are imported by the translocase of the outer mitochondrial membrane (TOM) and the presequ.

Figure 2: The presequence pathway into the mitochondrial inner membrane (IM) and matrix. The translocase of the outer membrane (TOM) consists of three receptor proteins, the channel-forming protein To.

Figure 3: Role of the oxidase assembly (OXA) translocase in protein sorting. Proteins synthesized by mitochondrial ribosomes are exported into the inner membrane (IM) by the OXA translocase the ribos.

Figure 4: Carrier pathway into the inner membrane. The precursors of the hydrophobic metabolite carriers are synthesized without a cleavable presequence. The precursors are bound to cytosolic chaperon.

Figure 5: Mitochondrial intermembrane space import and assembly (MIA) machinery. Many intermembrane space (IMS) proteins contain characteristic cysteine motifs. The precursors are kept in a reduced an.

Figure 6: Biogenesis of β-barrel proteins of the outer mitochondrial membrane. The precursors of β-barrel proteins are initially imported by the translocase of the outer membrane (TOM), bind to small .

Figure 7: The dual role of mitochondrial distribution and morphology protein 10 (Mdm10) in protein assembly and organelle contact sites. Mdm10 associates with the sorting and assembly machinery (SAM) .

Figure 8: Multiple import pathways for integral α-helical proteins of the mitochondrial outer membrane. The precursors of proteins with an N-terminal signal anchor sequence are typically inserted into.

Figure 9: The mitochondrial contact site and cristae organizing system (MICOS) interacts with protein translocases. MICOS consists of two core subunits, Mic10 and Mic60. Mic10 forms large oligomers th.


Beta-Lactam Antibiotics: Mechanism of Action, Resistance

The beta-lactam ring is key to the mode of action of these drugs that target and inhibit cell wall synthesis by binding the enzymes involved in the synthesis. These enzymes are anchored in the cell membrane and as a group is referred to as penicillin-binding proteins (PBPs). Bacterial species may contain between 4-6 different types of PBPs. The PBPs involved in cell wall cross-linking (i.e.,transpeptidases) are often the most critical for survival.

The 4-member ring of beta-lactam antibiotics gives these compounds a three-dimensional shape that mimics the D-Ala-D-Ala peptide terminus that serves as the natural substrate for transpeptidase activity during cell wall peptidoglycan synthesis. Tight binding of these beta-lactam drugs to the transpeptidase active site inhibits cell wall synthesis. Death results from osmotic instability caused by faulty cell wall synthesis, or the binding of the beta-lactam to PBP may trigger a series of events that lead to autolysis and death of the cell. Mechanism of action of beta-lactam antibiotics

Beta-lactam agents are active against both gram-positive and gram-negative bacteria but effectiveness varies owing to structural differences in cell-wall structure (e.g., the outer membrane present in gram-negative but not gram-positive bacteria) and PBP content.

Resistance mechanisms against Beta-Lactams Antibiotics

Three pathways play an important role to confer resistance to beta-lactams. They are enzymatic destruction of the antibiotics, altered antibiotic targets, or decreased uptake of the drug.

Summary

Enzyme destruction of the antibiotics

Hydrolysis of penicillins & cephalosporin antibiotics by β-lactamase

Destruction of beta-lactams by beta-lactamase enzyme-producing bacteria is by far the most important method of resistance. Beta-lactamases open the beta-lactam ring and the altered structure of the drug can no longer bind to PBPs and is no longer to inhibit cell wall synthesis. But not all β-lactams are susceptible to hydrolysis by every β-lactamase. For example, staphylococcal beta-lactamase can readily hydrolyze penicillin and penicillin derivative but fails to hydrolyze many cephalosporins and imipenem.

Do you know?

Both gram-positive and gram-negative bacteria produce β-lactamase. β-lactamases produced by gram-positive bacteria are secreted into the surrounding environment but that of gram-negative bacteria remains in the periplasmic space.

Altered antibiotic targets

The organisms change or acquire a gene that code for altered PBPs. β-lactams lack sufficient affinity for the altered PBP, thus can not prevent their function (i.e. cell wall synthesis continues even in the presence of antibiotics. For example, methicillin-resistant Staphylococcus aureus (MRSA) developed resistance to methicillin and all other β-lactams using this mechanism. β-lactam resistance mechanisms of gram-positive and gram-negative bacteria.
Image source (Bailey & Scott’s Diagnostic Microbiology)


SOURCES AND CLASSES/TYPES OF ANTIBIOTICS

Before the advent of conventional medicine used in clinical medicine today for the treatment of infectious diseases, people in ancient times and even now have been using some herbal plants traditionally for centuries to combat microbes that cause diseases in man. Recently, scientists have studied and reported results that support the use of these herbal plants. Herbal antibiotics have been found to be milder than pharmaceutical antibiotics, and according to the Center for Disease Control and Prevention (CDC), the overuse of pharmaceutical antibiotics cause pathogens to mutate and grow stronger, giving them the chance to mount resistance to antibiotics. Some of the herbal plants used for the treatment of infectious diseases in most rural parts of the developing world (especially in places where conventional drugs may not readily be available) include but not limited to: Neem plant (Azadirachta indica), Ginger, Garlic, Tea Tree Plant and Moringa oleifera plant.

MAJOR SOURCES OF ANTIBIOTICS

  1. MICROORGANISMS: Microorganisms are the primary source of antibiotics. Though not all antibiotics used today in clinical medicine are produced completely (wholly) from microorganisms, microorganisms still provide the parent root from which antibiotics are developed. Bacitracin and polymyxins are obtained from Bacillus species streptomycin and tetracycline are obtained from Streptomyces species gentamicin from Micromonospora purpurea penicillins and cephalosporins are obtained from Penicillium and Cephalosporium species respectively.
  2. Synthetic antibiotics: Synthetic antibiotics are antibiotics produced from natural drugs by making a prototype (model) of the natural drug in the laboratory through chemical reactions without having to do anything with the original source of the drug. Example of a synthetic antibiotic is chloramphenicol.
  3. Semi-synthetic antibiotics: Semi – synthetic antibiotics are natural antibiotics that are modified by the removal or addition of a particular chemical group in order to increase the therapeutic effect of the drug. Here, compounds isolated from natural sources (e.g. plants or microorganisms) are used as starting materials and a fermentation process is involved in the production of such antibiotics. After which, the antibiotic is further modified by a chemical process in the laboratory. Examples of drugs produced this way include: penicillins, cephalosporins, and the anti-malarial drug, artemether.

CLASSES/TYPES OF ANTIBIOTICS

There are several classification/types of antibiotics today, which is based on bacterial spectrum of activity (whether broad or narrow) or type of activity exhibited by the agent (whether bactericidal or bacteriostatic). Some antibiotics are also classified based on their chemical structure. And this leaves antibiotics within a particular structural class to have similar patterns of effectiveness, toxicity, and allergic potential. The types of antibiotics expanded here are not exhaustive of the different classes or types of antibiotics.

  1. BETA – LACTAM ANTIBIOTICS: The beta – lactam antibiotics are a broad class of antibiotics that consist of all antibiotic agents that contains a beta – lactam ring/nucleus in its molecular structure. They are the oldest class of antibiotics especially the penicillins and they are produced from Penicillium and Cephalosporium bacteria.Examples of antibiotics in this class include: penicillins, cephalosporins, monobactams and carbapenems. The beta – lactam antibiotics work by inhibiting the synthesis of cell wall in bacteria. They are the most widely used group of antibiotics in clinical medicine, and they are active on both Gram-positive and Gram-negative bacteria. Beta – lactam antibiotics have no antibacterial activity on bacterial cells that lack cell wall e.g. Mycoplasmas. They are only effective on bacterial species that have cell wall, and are actively growing.
  2. MACROLIDES: The macrolides are a group of antibiotics that are characterized by possessing molecular structures that contain large (12-16 membered) lactone rings linked through glycosidic bonds with amino sugars. They are derived from Streptomyces bacteria and they are bacteriostatic, binding with bacterial ribosomes to inhibit protein synthesis. Macrolides are active against most Gram-positive bacteria but not against the Enterobacteriaceae. Examples of antibiotics in this category include: erythromycin, azithromycin, and clarithromycin.
  3. FLUOROQUINOLONES: The fluoroquinolones (fluorinated – quinolones) are second – generationquinolones that are produced by the addition of a fluorine atom (molecule) on the carbon-6 (C-6) of quinolones. They are synthetic antibiotics and are not sourced from microorganisms. Nalidixic acid is the first quinolone while ciprofloxacin, ofloxacin and norfloxacin are examples of fluoroquinolones. They are active on both Gram-positive and Gram-negative bacteria, and they are mostly used in the treatment of urinary tract infections (UTIs). The fluoroquinolones target the DNA gyrase and topoisomerase IV enzymes of bacterial cell, leading to the inhibition of DNA synthesis or replication. Thus, the fluoroquinolones inhibit bacteria by interfering with their ability to make DNA. This activity makes it difficult for bacteria to multiply and cause havoc in vivo. They are used to treat most UTIs, skin infections, and respiratory infections because of their excellent absorption in vivo.
  4. TETRACYCLINES: The tetracyclines are a group of antibiotics that is characterized by a four cyclic ring. They are derived from a group of Streptomyces bacteria and they inhibit bacterial protein synthesis. Examples include oxytetracycline, doxycycline and chlortetracycline. Tetracyclines have a wide range of activity on both Gram-positive and Gram-negative bacteria. They are broad spectrum bacteriostatic agents.
  5. AMINOGLYCOSIDES: Aminoglycoside antibiotics contain amino sugars in their structures and they possess a cyclohexane ring. They are derived from Streptomyces bacteria, and they are bactericidal in action. Aminoglycosides inhibit the synthesis of protein in bacterial cell. Examples of antibiotic in this category include gentamicin, kanamycin, tobramycin and streptomycin.

Ashutosh Kar (2008). Pharmaceutical Microbiology, 1 st edition. New Age International Publishers: New Delhi, India.

Block S.S (2001). Disinfection, sterilization and preservation. 5 th edition. Lippincott Williams & Wilkins, Philadelphia and London.

Courvalin P, Leclercq R and Rice L.B (2010). Antibiogram. ESKA Publishing, ASM Press, Canada.

Denyer S.P., Hodges N.A and Gorman S.P (2004). Hugo & Russell’s Pharmaceutical Microbiology. 7 th ed. Blackwell Publishing Company, USA. Pp.152-172.

Ejikeugwu Chika, Iroha Ifeanyichukwu, Adikwu Michael and Esimone Charles (2013). Susceptibility and Detection of Extended Spectrum β-Lactamase Enzymes from Otitis Media Pathogens. American Journal of Infectious Diseases. 9(1):24-29.

Finch R.G, Greenwood D, Norrby R and Whitley R (2002). Antibiotic and chemotherapy, 8 th edition. Churchill Livingstone, London and Edinburg.

Russell A.D and Chopra I (1996). Understanding antibacterial action and resistance. 2 nd edition. Ellis Horwood Publishers, New York, USA.


GENERAL MECHANISM OF ACTION OF ANTIBIOTICS

Antibiotics are used to treat infections caused by disease causing microorganisms (e.g., pathogenic bacteria). Majority of them exert a highly selective toxic action upon their target microbial cells but have little or no toxicity towards mammalian cells. These antibiotics can therefore be administered at concentrations sufficient enough to kill or inhibit the growth of infecting organisms without damaging mammalian cells. The ways by which these antibiotics exert their antibacterial activities on their target microbes in vivo without necessarily harming the host (patient) taking the drug is called the “Mechanism of Action of Antibiotics”. It reveals and explains the rationale behind the selective toxicity of antibiotics and how they stop the venomous effects of bacteria.

Selective toxicity is the ability of antibiotics (antimicrobial agents) to kill or inhibit the growth of microorganisms (in vivo)without causing any untoward effect to the host taking the agent (drug). It is the ability of an antimicrobial agent to kill or inhibit a microbial pathogen while damaging the host as little as possible. For antibiotics to be therapeutically relevant for use against a particular pathogen in vivo, it must be selectively toxic in nature. Antimicrobial agents (in particular antibiotics) show a wide variety of mechanisms of action against pathogenic microorganisms either in vivo or in vitro and these shall be discussed in this section. The mechanism of action elaborated here is strictly for antibacterial agents (i.e. drugs that target pathogenic bacteria).

  • INHIBITION OF MICROBIAL CELL WALL SYNTHESIS: Peptidoglycan is a vital component of the cell wall of virtually all bacteria with exception to wall-less bacteria such as mycoplasmas that lack cell wall. But it is more pronounced in Gram-positive bacteria than in Gram-negative bacteria. The peptidoglycan layer is responsible for maintaining the shape and mechanical strength of the bacterial cell wall. If it is damaged in anyway, or its synthesis is inhibited (e.g. by antibiotics), then the shape of the bacterial cells becomes distorted and they will eventually burst (lyse) due to the high internal osmotic pressure following the influx of fluids or substances like drugs from the outside into the bacterial cell. Mammalian cell is devoid of peptidoglycan layern, thus antibiotics which inhibit microbial cell wall synthesis show outstanding selective toxicity. Examples of antibiotics that inhibit bacterial cell wall synthesis include: penicillins, bacitracin, glycopeptides (e.g. vancomycin), and cephalosporins.

These antibiotics stop the cross-linking of N-acetyl-glucosamine (NAG) and N-acetyl-muramic acid (NAM) via a reaction known as transpeptidation reaction. This cross-linking is supposed to lead to the formation of peptidoglycan, an important component of bacterial cell wall. Bacterial resistance to beta-lactam antibiotics (e.g. penicillins and cephalosporins) is one of the mechanisms used by pathogenic bacteria (both Gram-positive and Gram-negative organisms) to evade the antimicrobial onslaught of beta-lactam drugs and this is because these antibiotics (i.e. beta-lactams) are the most widely used drugs in clinical medicine. However, the growing level of bacterial resistance towards these potent antibiotics is fast slowing the efficacy and clinical applications of these agents. Beta-lactam antibiotics as earlier explained are a class of drugs that inhibit the synthesis of cell wall in pathogenic bacteria. The antibacterial activity of beta-lactams is exhibited in vivo when the drugs bind to specific receptors on the cell membrane or cell wall of the target bacterium especially the penicillin-binding-proteins (PBPs).

Binding of beta-lactam antibiotics to the PBPs of pathogenic bacteria prevent the cross-linking of NAM and NAG. NAG and NAM are both vital for the synthesis of peptidoglycan layer, an important component of bacterial cell wall. The synthesis of peptidoglycan layer is inhibited once the cross-linking of NAM and NAG is hindered via the antibacterial action of beta-lactam antibiotics. And this renders the bacterial cell wall porous to external harmful substances such as drugs, water and other chemicals. The bacterial cell eventually dies following rupture or lysis of the cell. Nevertheless, pathogenic bacteria produce antibiotic-hydrolyzing enzymes such as beta-lactamases which render beta-lactam drugs inefficacious in vivo. Beta-lactam antibiotics are unique because they have a ring known as the beta-lactam ring, and which is the target of the beta-lactamases produced by pathogenic bacteria. The beta-lactamase enzyme cleaves the carbon-nitrogen (C-N) bond of the beta-lactam ring of beta-lactams and this eventually leads to the production of a compound with a lesser antibacterial activity. In the case of penicillin for example, cleavage of the beta-lactam ring of the penicillins leads to the formation of penicilloic acid which is devoid of any antibacterial activity. Pathogenic bacteria that produce beta-lactamases as well as other expanded spectrum enzymes such as extended spectrum beta-lactamases (ESBLs) render beta-lactam antibiotics inefficacious in vivo and this is because of the antibiotic-hydrolyzing enzymes which they produce.

  • INHIBITION OF DNA SYNTHESIS FUNCTION: Deoxyribonucleic acid (DNA) is a vital component of the chromosome of bacterial cells as they are known to direct the activity of the cells. Antibiotics that inhibit the synthesis of DNA in bacterial cell work by interfering with the transcription stages which are very vital to the final and complete formation of bacterial DNA. These antibiotics block the DNA gyrase enzyme (topoisomerase II or IV) which is vital for the complete synthesis of DNA in bacteria. Examples of antibiotics that inhibit bacterial DNA synthesis function include: sulfonamides, trimethoprim, rifampicin, quinolones, and fluoroquinolones.
  • DESTRUCTION OF MICROBIAL CELL MEMBRANE: The integrity of the cytoplasmic (cell) membrane in bacterial cell is very important for the normal functioning of all cells. Bacterial cell membranes do not contain sterols. This differentiates them from fungal and mammalian cells which do contain sterols, thus giving such antibiotics a highly selective toxicity on bacteria. Antibiotics that destroy the cytoplasmic membrane of bacterial cells cause irreversible leakage of cytoplasmic components by disturbing the integrity of the membrane. This can also impair other metabolic functions associated with the membrane. Examples of antibiotics that destroy microbial cell membrane include: polymyxins (which target bacterial cell membrane), and polyenes (which target fungal cell membranes).
  • INHIBITION OF PROTEIN SYNTHESIS: Bacterial ribosomes are smaller than their mammalian counterparts. The ribosomes in bacterial cells are vital for the synthesis of proteins. Antibiotics that inhibit the synthesis of protein in bacterial cells act by binding to a receptor on either the 30S or 50S subunit ribosomes. This action prevents the complete reaction of translocation, thereby inhibiting the synthesis of protein in bacterial cells. Antibiotics that are protein synthesis inhibitors include: tetracyclines, chloramphenicol, macrolides, and streptomycin.
  • INHIBITION OF METABOLIC PATHWAY: The inhibition of a metabolic pathway in microbes (e.g. a pathway responsible for synthesizing key metabolites such as folic acid) is carried out by a group of antibiotics known as anti-metabolites. These antibiotics inhibit the production of key metabolites in their target organisms. Antibiotics that are anti-metabolites include: sulphonamides, trimethoprim and pyrimethamine. Anti-metabolites block the key steps in folate synthesis. Folate is an important cofactor in the biosynthesis of nucleotides which are the building blocks of DNA and RNA in microorganisms. Sulphonamides are structural analogues of para-aminobenzoic acid (PABA). PABA is a key component in the synthesis of folic acid in bacteria. They competitively block the conversion of pteridine and PABA to dihydrofolic acid because the anti-metabolite, sulphonamides has a greater affinity for the enzyme (dihydropterate synthetase) that performs the conversion than does PABA. Bacteria and protozoa unlike most mammalian or animal cells (which obtain their own folic acid from their diet) synthesize their own folic acid. Sulphonamides competitively inhibit the incorporation of PABA into dihydropteroic acid (folic acid), and once this is done, folic acid will no longer be available for the synthesis of purines and pyrimidines which are both required for the coupling of bacteria DNA and RNA. This inhibits the synthesis of nucleic acid in the organism.

Ashutosh Kar (2008). Pharmaceutical Microbiology, 1 st edition. New Age International Publishers: New Delhi, India.

Block S.S (2001). Disinfection, sterilization and preservation. 5 th edition. Lippincott Williams & Wilkins, Philadelphia and London.

Courvalin P, Leclercq R and Rice L.B (2010). Antibiogram. ESKA Publishing, ASM Press, Canada.

Denyer S.P., Hodges N.A and Gorman S.P (2004). Hugo & Russell’s Pharmaceutical Microbiology. 7 th ed. Blackwell Publishing Company, USA. Pp.152-172.

Ejikeugwu Chika, Iroha Ifeanyichukwu, Adikwu Michael and Esimone Charles (2013). Susceptibility and Detection of Extended Spectrum β-Lactamase Enzymes from Otitis Media Pathogens. American Journal of Infectious Diseases. 9(1):24-29.

Finch R.G, Greenwood D, Norrby R and Whitley R (2002). Antibiotic and chemotherapy, 8 th edition. Churchill Livingstone, London and Edinburg.

Russell A.D and Chopra I (1996). Understanding antibacterial action and resistance. 2 nd edition. Ellis Horwood Publishers, New York, USA.


Total synthesis of .beta.-lactam antibiotics. Epimerization of 6(7)-aminopenicillins and cephalosporins from .alpha. to .beta.

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.beta.-Lactam antibiotics from Streptomyces

Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.

Note: In lieu of an abstract, this is the article's first page.



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