Effect of Environment on Growth Kinetics- Temperature

Growth kinetics can be affected by three main environmental factors:

1. Temperature
2. pH
3. Dissolved oxygen concentration

Temperature

    According to temperature optima (T_opt), organisms are classified into three types:

•     Psychrophiles (T_opt < 20°C)
•     Mesophiles (T_opt  50°C-80°C)
•     Thermophiles (T_opt > 50°C)

 Figure 1: Schematic representation of effect of Temperature in growth

      Now, As the temperature increase towards this optimal growth temperature, the growth rate actually doubles for every 10 degree Celsius. 

Please look into the figure above. Consider the Car is the cell and as it moves towards the optimal growth temperature, its growth rate i.e µg doubles for every 10 degree Celsius increase in temperature. 

but, beyond this optimal temperature, µg drops slowly and finally thermal death occurs. So What could be the net replication rate for temperature above optimal level?

First the net replication rate in the absence of cell death i.e kd is said to be 

N (µ’R) = dN/dt

Now thermal death occurs above the optimal growth temperature and that could be explained by another equation. i.e

N (-k'd) =dN/dt

Combining both these equation, we get 

dN/dt = (µ’R - k'd) N

So, at higher temperature the thermal death rate exceeds the growth rate, which causes a net decrease in the concentration of viable cells. 
    
 Both the net replication rate constant and death rate constant vary with temperature which is according to Arrhenius Equation. 

µ’R = Ae^(-Ea/RT)
k’d = A'e^(-Ed/RT)

Ea and Ed are the activation energies for growth and thermal death.
For growth Ea is 10-20 kcal/mol and thermal death Ed is 60-80 kcal/mol. So, Thermal death is more sensitive to temperature changes than microbial growth.

     Temperature affects four things:

   Why maintenance coefficient increase with increase in temperature?

   

   As the temperature increases, the proteins and cell organelles starts to ware out and in order to replace the losses, the cell utilizes more of the substrate. 

      

    Maintenance Coefficient is the specific rate of substrate uptake for cellular maintenance. And increase in 'm' happens with activation energy range between 15-20 kcal/mol, which results in decrease in the yield coefficient. 

 
 
 
 

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Complement system

Activities of complement system

Lysis, opsonisation, activation of inflammatory response, clearance of immune complexes. They are produced by liver hepatocytes and small amount by blood monocytes, macrophage, and epithelial cells. Zymogens are inactive form of complement proteins and they are activated by proteolytic cleavage which removes the inhibitory fragment and exposes the active site of molecule.

There are three pathways of complement activity

1. Classical pathway
2. Alternative pathway
3. Lectin pathway

The common among all these pathways is the formation of MAC (membrane attacking complex). 

1. Classical pathway

The activation starts with formation of soluble antigen antibody complexes or with the binding of antibody to antigen on a suitable target. IgM and IgG activate the complement pathway and initial stage of activation involves components C1, C2, C3, and C4 which are present in plasma in functionally inactive forms.

Fc portion of IgM conformational change on binding of antigen. Exposure site on IgM for C1 complement protein to bind. C1 consists of C1qr₂s₂ held together in a complex stabilized by calcium ions.

C1q molecule à 18 polypeptide chains that associate to form six collagen like triple helical arms, tips of which bind to exposed C1q binding sites in C_H2 domain of the antibody molecule.

Each C1r and C1s monomer contains a catalytic domain and an interaction domain, the latter facilitates interaction with C1q or with each other.

After the C1q is bound to Fc binding sites, a conformational changes induce C1r to become a active serine protease enzyme C1r* which then cleaves C1s to a similar active enzyme C1s*.

C1s* à two substrates C4 and C2. The C4 is glycoprotein contains three polypeptide chains α, β, and γ.

C4 is activated when C1s* hydrolyzes a small fragment C4a from the amino terminus of α chain, exposing a binding site on the larger fragment (C4b).

The C4b fragment attaches to the target surface in the vicinity of C1 and the C2 proenzyme then attaches to the exposed binding site on C4b, where the C2 is then cleaved by the neighbouring C1s*, the small fragment C2b diffuses away.

The resulting C4b2a* complex is called C3 convertase.

C3 convertase converts C3 into active form. C4a is an anaphylatoxin or mediator of inflammation which does not participate directly in the lytic function of the complement cascade. Similarly C3a and C5a is also an anaphylatoxin.

The C3 component consists of two polypeptide chains α and β. Hydrolysis of a short fragment C3a from the amino terminus of α chain by the C3 convertase generates C3b.

Some C3b component binds to C4b2a* complex to form a trimolecular complex called C5 convertase (C4b2a3b*).

C3b component of this complex binds C5 and alters its conformation allowing C4b2a* component to cleave C5 into C5a, which diffuses away and C5b which attaches to C6 and initiates formation of the membrane attack complex.

C3b sometimes function as opsonin and promote phagocytosis. C3b may also bind directly to cell membranes.

2. Alternative pathway

It happens similar to the classical pathway, but it does without the antigen antibody complexes for initiation. Since, it is a component of innate immunity.

It involves four serum proteins C3, factor B, factor D and properdin.

Serum C3 gets cleaved into C3a and C3b on the microbial cell surface.

The C3b bind to either foreign surface antigens or to the host cell. But on the host cell is not affected by C3b binding because host cell surface is having high sialic acid which contributes to rapid inactivation of bound C3b molecules on host cells.

Then another serum protein called factor B forms complex with C3b and it is stabilized by Mg²⁺.

Now this complex serve as a substrate for factor D, which convert them into C3bBb* complex.

The complex is having C3 convertase activity which is limited half life unless the serum protein properdin binds to it. 

Now the C3 convertase cleaves the C3 into C3b and C3a. C5 convertase is formed by the binding of C3b to the C3 convertase (C3bBbC3b). C5 convertase generates C5a and C5b. C5b is used for MAC. 

3. Lectin pathway

Lectins are proteins that recognize and bind to specific carbohydrate targets. Lectin activates complements binds to mannose residues.

Lectin pathway is activated by the binding of mannose binding lectin to mannose residues on glycoproteins or carbohydrates on the surface of microorganisms, including bacteria such as salmonella, listeria and neisseria strains.

MBL is a collectin family acute phase proteins and its concentration increases during inflammatory responses. Its function in the complement pathway is similar to that of C1q, which it resembles in structure.

After MBL binds to the carbohydrates residues on the surface of cell or pathogen, MBL associated serine proteases, MASP-1 and MASP-2 bind to MBL.

Now the active complex formed by this association causes cleavage and activation of C4 and C2. MASP-1 and MASP-2 are structurally similar to C1r and C1s and mimic their activity. 

MAC formation 

C5b, C6, C7, C8, and C9 which interact sequentially to form a macromolecular structure called the membrane attack complex (MAC). It forms a large channel on the membrane of the target cell enabling ions and small molecules to diffuse freely across the membrane.

C3b and C4b binding facilitates opsonisation.

Complement system neutralize viral infectivity. 

Regulation of complement system

C1 inhibitor à form complex with C1r2s2 causing it to dissociate from C1q and preventing further activation of C4 or C2.

C3b is hydrolysed once it moves away at 40 nm distance from the C4b2a* or C3bBb* convertase enzymes.

C3 convertase activity is regulated by proteins which contain repeating amino sequences of about 60 residues termed short consensus repeats (SCRs). All this proteins are encoded in single location on chromosome 1 in humans, known as the regulators of complement activation (RCA) gene cluster.

RCA proteins prevent C3 convertase assembly and it includes proteins like C4b binding protein (C4bBP), and two membrane bound proteins, complement receptor type 1 (CR1) and membrane cofactor protein (MCP).

Each of these regulatory proteins binds to C4b and prevents its association with C2a. Once the regulatory proteins binds to C4b, another regulatory protein factor I cleaves the C4b into bound C4d and soluble C4c.

In other case, MCP, CR1 and Factor H binds to C3b and prevents it association with factor B. After this, Factor I cleaves C3b into a bound iC3b and release C3c fragment.

Decay accelerating factor (DAF or CD55) which is a glycoprotein covalently anchored to a glycophospholipid membrane protein has the ability to dissociate C3 convertase.

Homologous restriction factor (HRF) or membrane inhibitor of reactive lysis (MIRL or CD59). CD59 protects cells from nonspecific complement mediated lysis by binding to C8 preventing assembly of poly C9 and its insertion into plasma membrane.  

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Immune organs: Primary and Secondary Lymphoid organs

Primary lymphoid organs à maturation of lymphocytes takes places.

Thymus

It is the site for T cell development and maturation.

Bilobed organ situated above the heart. Each lobe is surrounded by a capsule and divided into lobules, which are separated from each other by strands of connective tissue called trabeculae. Each lobule is organized into two compartments: cortex which is densely packed with immature T cells called Thymocytes whereas the inner compartment or medulla is sparsely populated with thymocytes.

Both the compartments consist of epithelial cells, dendritic cells, and macrophages which make up the framework of the organ and contribute to the growth and maturation of thymocytes.

Function of thymus: to generate and select a repertoire of T cells that will protect the body from infection. As thymocytes develop, enormous diversity of T cell receptors is generated by gene rearrangement. 

It produces some T cells with receptors capable of recognizing antigen MHC complexes. But only small portion of cells survive and rest will undergo apoptosis. 

Bone marrow

It is a complex tissue that is the site of haematopoiesis and a fat depot. Hematopoietic cells are generated here move through the walls of blood vessels and enter the bloodstream, which carries them out of the marrow and distributes these various cell types to the rest of the body.

It is site of B cell origin and development. Immature B cells proliferate and differentiated within the Bone marrow and stromal cells within the bone marrow interact directly with the B cells and secrete various cytokines that are required for development. 

Secondary lymphoid organs à site for mature lymphocytes to interact with antigen.

Lymphatic system

lymphoid follicles: primary follicle à network of follicular dendritic cells and small resting B cells. After antigenic challenge, a primary follicle becomes secondary follicle à a ring of concentrically packed B lymphocytes surrounding a center (the germinal center) in which one finds a focus of proliferating B lymphocytes and an area that contains nondividing B cells and some helper T cells interspersed with macrophages and follicular dendritic cells.

Lymph nodes and spleen à surrounded by fibrous capsules.

MALT à less organized lymphoid tissue found in various body sites.

Lymph node:

Encapsulated bean shaped structures containing a reticular network packed with lymphocytes, macrophages and dendritic cells. They are organised in such a way to encounter antigens that enter the tissue spaces.

Cortex à outermost layer contains B cells mostly, macrophages and follicular dendritic cells arranged in primary follicles. After antigenic challenge, the primary follicles enlarge into secondary follicles, each containing germinal center.

Paracortex à it is beneath cortex which is populated largely by T cells and also contains dendritic cells that migrated from tissue to the node.

Medulla à more sparsely populated with lymphoid lineage cells, and of those present, many are plasma cells actively secreting antibody molecules.

Lymph nodes traps the antigens from local tissues.

Spleen:

Present in the high left abdominal cavity. It is large ovoid, plays a major role in mounting immune responses to antigens in the blood stream.  Spleen filters the blood and traps the blood borne antigens. So it responds to systemic infections. It is not supplied by lymphatic vessels, instead antigens and cells are carried into spleen through splenic artery.  It is surrounded by capsules from which a number of projections extend into the interior to form a compartmentalized structure.

Two compartments:

Red pulp: network of sinusoids populated by macrophages, numerous red blood cells, and few lymphocytes. Defective and old RBCs are destroyed and removed.

White pulp: it surrounds a branches of splenic artery forming a periarteriolar lymphoid sheath (PALS) populated mainly by T cells. Primary lymphoid follicles are attached to PALS.

Marginal zone contains lymphocytes and macrophages. Antigens are trapped in marginal zone by dendritic cells, which then carry it to the PALS. And also lymphocytes enter through the same route as of the antigen.

MALT (mucosa associated lymphoid tissue)

The vulnerable membrane surface of digestive, respiratory and urogenital systems are defended by a group of organized lymphoid tissues called MALT.

Respiratory epithelium à bronchus associated lymphoid tissue (BALT)

Epithelium of the digestive tract à Gut- associated lymphoid tissue (GALT)

MALT includes tonsils, and appendix.

M cells carry the antigen from lumina of the tracts to the underlaying MALT. They are flattened epithelial cells lacking the microvilli that characterize the rest of the mucous epithelium. They have deep invagination, or pocket in the basolateral, plasma membrane which is filled with a cluster of B cells, T cells and Macrophages. 

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NOD and Toll Like Receptor Protein

NOD proteins

Cytosolic and has two members in this family i.e. NOD1 and NOD2, which recognize products derived from bacterial peptidoglycans.

NOD1 binds to the tripeptide products of peptidoglycans (NAM and NAG) breakdown and NOD2 recognizes muramyl dipeptide, derived from the degradation of peptidoglycan from gram positive bacterial cell walls.

NOD1 recognizes meso-diaminopimellic acid (meso-DAP) in Gram –ve bacteria and NOD2 senses intracellular muramyl dipeptide (MDP) in S. Pneumoniae and M.tuberculosis.

Mutation of NOD2 is associated with crohn’s disease or Blau syndrome. 

Toll Like Receptor proteins (TLR)

Membrane spanning proteins that share a common structural element in their extracellular region, repeating segments of 24 to 29 amino acids containing the sequence xLxxLxLxx. These structural motifs are called leucine rich repeats. The intracellular domain of TLR is called TIR domain.

TLR1 à ligand is Triacyl lipopeptides and a target microbe is mycobacteria.

TLR2 à ligand is peptidoglycans, GPI linked proteins, lipoproteins and zymosan. Target molecules are gram positive bacteria, trypanosomes, mycobacteria, yeasts and other fungi.

TLR3 à double stranded RNA (dsRNA) and target microbes are viruses.

TLR4 àLPS and F-protein and target microbes are Gram –ve and respiratory syncytial virus (RSV)

TLR5 à flagellin and target is bacteria.

TLR6 à diacyl lipopeptides and zymosan. Mycobacteria, yeast and fungi.

TLR7 à single stranded RNA (ssRNA) and viruses.

TLR8 à single stranded RNA (ssRNA) and viruses.

TLR9 à CpG unmethylated dinucleotides, dinucleotides, herpesvirus infection. Bacterial DNA and some herpesvirus

TLR10 and TLR11 à unknown 

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Innate immunity

Its a non specific immunity. 

It’s not long lasting defense system like adaptive immunity, but provides immediate defense against infection.

First line of defense against foreign organisms

Cells involved in innate immunity are  mast cells, phagocytic cells like macrophages, neutrophiles, dendritic cells, basophiles and eosinophiles, natural killer cells, γδ T cells.

Barriers which prevent the entry or growth of microorganisms inside the body: Skin, Phagocytic cells, Antibacterial proteins such as α defensin, Psoriasin.

Psoriasin is a small protein with potent antibacterial activity against E.Coli.

Anatomical barriers are skin which defense against the microorganism through the sweat, desquamation, flushing and organic acids. GI tract, which has defensin, gut flora, thiocynate, bile acids, gastric juice, and peristalsis. Airway and lungs has surfactant, mucociliary elevator. Eyes have tears. Nasopharynx has mucus, saliva, lysozyme.

C- Reactive protein belongs to family of pentameric proteins called pentraxins, which bind ligands in a calcium dependent reaction.

BPI (bactericidal/permeability-increasing protein) is 55 kDa proteins that bind with high affinity to LPS in the walls of gram negative bacteria and cause damage to the bacterium’s inner membrane.

iNOS (inducible nitric oxide synthetase), an enzyme that oxidizes L- arginine to yield L- citrulline and Nitric oxide (NO).

ROS species production

Oxygen O2 à .O₂^- à H₂O₂ à HClO^-

Oxygen is converted to superoxide anion by NADPH phagosome oxidase, and then Superoxide anion is converted to hydrogen peroxide by superoxide dismutase. Then with addition of chlorine ion, hydrogen peroxide is converted to hypochlorite by myeloperoxidase.

Natural killer cells produce interferon gamma and TNF alpha. These cytokines stimulate the maturation of dendritic cells. INFG is a mediator of macrophage activation and regulator of T helper cells development. 

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How Selenocysteine is incorporated into polypeptide chain during translation?

1. No free pool of Selenocysteine exists in the cell.


2. Its high reactivity would incur damage to cells. Instead, cells store selenium in the less reactive selenide form (H₂Se).


3. Selenocysteine synthesis occurs on a specialized tRNA, which also functions to incorporate it into nascent polypeptides.


4. The primary and secondary structure of Selenocysteine tRNA, tRNA(Sec), differ from those of standard tRNAs in several respects, most notably in having an 8-base (bacteria) or 10-base (eukaryotes) pair acceptor stem, a long variable region arm, and substitutions at several well-conserved base positions.


5. The Selenocysteine tRNAs are initially charged with serine by seryl-tRNA ligase, but the resulting Ser-tRNA(Sec) is not used for translation because it is not recognized by the normal translation factor (EF-Tu in bacteria, eEF1A in eukaryotes). Rather, the tRNA-bound seryl residue is converted to a selenocysteine-residue by the pyridoxal phosphate-containing enzyme selenocysteine synthase.


6. Finally, the resulting Sec-tRNA(Sec) is specifically bound to an alternative translational elongation factor (SelB or mSelB (a.k.a. eEFSec)), which delivers it in a targeted manner to the ribosomes translating mRNAs for selenoproteins.


7. The specificity of this delivery mechanism is brought about by the presence of an extra protein domain (in bacteria, SelB) or an extra subunit (SBP2 for eukaryotic mSelB/eEFSec) which bind to the corresponding RNA secondary structures formed by the SECIS elements in selenoprotein mRNAs.

There are more than 20 human proteins that contain Selenocysteine.

where does Selenocysteine comes from?

Selenocysteine is not coded for directly in the genetic code. Instead, it is encoded in a special way by a UGA codon, which is normally a stop codon. When cells are grown in the absence of selenium, translation of selenoproteins terminates at the UGA codon, resulting in a truncated, nonfunctional enzyme.

The UGA codon is made to encode Selenocysteine by the presence of a SECIS element (Selenocysteine Insertion Sequence) in the mRNA. The SECIS element is defined by characteristic nucleotide sequences and secondary structure base-pairing patterns. In bacteria, the SECIS element is located immediately following the UGA codon within the reading frame for the selenoproteins. In archaea and in eukaryotes, the SECIS element is in the 3' untranslated region (3' UTR) of the mRNA, and can direct multiple UGA codons to encode Selenocysteine residues.

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Inhibitors of DNA Replication in Eukaryotic cells

DOXORUBICIN

The exact mechanism of action of doxorubicin is complex and still somewhat unclear, though it is thought to interact with DNA by intercalation. Doxorubicin is known to interact with DNA by intercalation and inhibition of macromolecular biosynthesis. This inhibits the progression of the enzyme topoisomerase II, which relaxes supercoils in DNA for transcription. Doxorubicin stabilizes the topoisomerase II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being resealed and thereby stopping the process of replication.

The planar aromatic chromophore portion of the molecule intercalates between two base pairs of the DNA, while the six-membered daunosamine sugar sits in the minor groove and interacts with flanking base pairs immediately adjacent to the intercalation site, as evidenced by several crystal structures.

Intercalation occurs when ligands of an appropriate size and chemical nature fit themselves in between base pairs of DNA.

ETOPOSIDE

Etoposide phosphate (brand names: Eposin, Etopophos, Vepesid, VP-16) is an anti-cancer agent. It inhibits the enzyme topoisomerase II, which unwinds DNA, and by doing so causes DNA strands to break.

Etoposide forms a ternary complex with DNA and the topoisomerase II enzyme, preventing re-ligation of the DNA strands. This causes errors in DNA synthesis and promotes apoptosis of the cancer cell.

CAMPTOTHECIN

Camptothecin (CPT)cytotoxic quinoline alkaloid which inhibits the DNA enzyme topoisomerase I. CPT binds to the topo I and DNA complex (the covalent complex) resulting in a ternary complex, and thereby stabilizing it. This prevents DNA re-ligation and therefore causes DNA damage which results in apoptosis. CPT binds both to the enzyme and DNA with hydrogen bonds.

Toxicity of CPT is primarily a result of conversion of single-strand breaks into double-strand breaks during the S-phase when the replication fork collides with the cleavage complexes formed by DNA and CPT

RIFAMPICIN

Rifampicin inhibits DNA-dependent RNA polymerase in bacterial cells by binding its beta-subunit, thus preventing transcription to RNA and subsequent translation to proteins. Its lipophilic nature makes it a good candidate to treat the meningitis form of tuberculosis, which requires distribution to the central nervous system and penetration through the blood-brain barrier.

Rifampicin acts directly on messenger RNA synthesis. It inhibits only prokaryotic DNA-primed RNA polymerase, especially those that are Gram-stain-positive and Mycobacterium tuberculosis. Much of this acid-fast positive bacteria's membrane is mycolic acid complexed with peptidoglycan, which allows easy movement of the drug into the cell. Evidence shows that in vitro DNA treated with concentrations 5000 times higher than normal dosage remained unaffected; in vivo eukaryotic specimens' RNA and DNA polymerases suffered few problems as well. Rifampicin interacts with the β subunit of RNA polymerase when it is in an α2β trimer. This halts mRNA transcription, therefore preventing translation of polypeptides. It should be made clear, however, that it cannot stop the elongation of mRNA once binding to the template-strand of DNA has been initiated. The Rifampicin-RNA polymerase complex is extremely stable and yet experiments have shown that this is not due to any form of covalent linkage. It is hypothesized that hydrogen bonds and π-π bond interactions between naphthoquinone and the aromatic amino acids are the major stabilizers, though this requires the oxidation of naphthohydroquinone which is found most commonly in Rifampicin. It is this last hypothesis that explains the explosion of multi-drug-resistant bacteria: mutations in therpoB gene that replace phenylalanine, tryptophan, and tyrosine with non-aromatic amino acids result in poor bonding between Rifampicin and the RNA polymerase.

Well due to blocking in RNA transcription, DNA initiation is also not possible since the primer synthesis is also blocked by the drug.

APHIDICOLIN

Aphidicolin is defined as a tetracyclic diterpene antibiotic with antiviral and antimitotical properties. Aphidicolin is a reversible inhibitor of eukaryotic nuclear DNA replication. It blocks the cell cycle at early S phase. It is a specific inhibitor of DNA polymerase A, D in eukaryotic cells and in some viruses and an apoptosis inducer in HeLa cells.

NOVOBIOCIN

The molecular basis of action of novobiocin, and other related drugs clorobiocin and coumermycin A1 has been examined. Aminocoumarins are very potent inhibitors of bacterial DNA gyrase and work by targeting the GyrB subunit of the enzyme involved in energy transduction. Novobiocin as well as the other aminocoumarin antibiotics act as competitive inhibitors of the ATPase reaction catalysed by GyrB. The potency of novobiocin is considerably higher than that of the fluoroquinolones that also target DNA gyrase, but at a different site on the enzyme. The GyrA subunit is involved in the DNA nicking and ligation activity.

CIPROFLOXACIN

Ciprofloxacin is a broad-spectrum antibiotic active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV, enzymes necessary to separate bacterial DNA, thereby inhibiting cell division.

1. Actinomycin -binding between adjacent G-C bases in DNA (intercalation
2. chloramphenicol- inhibits peptidyltransferase of the 70S ribosome
3. erythromycin - binds to the 50S particle and arrests synthesis of the 70S ribosome
4. neomycin- binds to the 30S ribosomal subunits and inhibits binding of a tRNA
5. puromycin- premature chain termination
6. Rifamycin- inhibits RNA synthesis by binding to the β subunit of the RNA polymerase holoenzyme
7. streptomycin as erythromycin
8. tetracyclin -inhibits binding of tRNA to the 30S ribosomal subunit in eukaryotes
9. α-amanitin - inhibits polymerase II
10. chloramphenicol - inhibits peptidyltransferase of the mitochondrial ribosome
11. cycloheximide -inhibits peptidyltransferase
12. diptheria toxin - inhibits factor 2 and translocation  

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Antimicrobial agents and mode of action

Antimicrobial agents are chemical substance that kills or inhibit the growth of microorganism such as bacteria, fungus and yeast. Most of this agents are found in the nature and some are artificial synthesized. They are used for sterilization of instruments, cultures or even wounds. 

Alexander Fleming is the first person to discover a natural antimicrobial agent i.e penicillin. After that vast number of agents are discovered or synthesized in the lab. 

Chemical class	Examples	Biological source	Spectrum (effective against)	Mode of action
Beta-lactams (penicillins and cephalosporins)	Penicillin G, Cephalothin	Penicillium notatum and Cephalosporium species	Gram-positive bacteria	Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly
Semisynthetic beta-lactams	Ampicillin, Amoxicillin		Gram-positive and Gram-negative bacteria	Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly
Clavulanic Acid	Augmentin is clavulanic acid plus Amoxicillin	Streptomyces clavuligerus	Gram-positive and Gram-negative bacteria	Inhibitor of bacterial beta-lactamases
Monobactams	Aztreonam	Chromobacterium violaceum	Gram-positive and Gram-negative bacteria	Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly
Carboxypenems	Imipenem	Streptomyces cattleya	Gram-positive and Gram-negative bacteria	Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly
Aminoglycosides	Streptomycin	Streptomyces griseus	Gram-positive and Gram-negative bacteria	Inhibits translation (protein synthesis)
	Gentamicin	Micromonosporaspecies	Gram-positive and Gram-negative bacteria esp.Pseudomonas	Inhibits translation (protein synthesis)
Glycopeptides	Vancomycin	Amycolatopsis orientalisNocardia orientalis(formerly designated)	Gram-positive bacteria, esp.Staphylococcus aureus	Inhibits steps in murein (peptidoglycan) biosynthesis and assembly
Lincomycins	Clindamycin	Streptomyces lincolnensis	Gram-positive and Gram-negative bacteria esp. anaerobicBacteroides	Inhibits translation (protein synthesis)
Macrolides	Erythromycin Azithromycin	Streptomyces erythreus	Gram-positive bacteria, Gram-negative bacteria not enterics, Neisseria, Legionella, Mycoplasma	Inhibit translation (protein synthesis)
Polypeptides	Polymyxin	Bacillus polymyxa	Gram-negative bacteria	Damages cytoplasmic membranes
	Bacitracin	Bacillus subtilis	Gram-positive bacteria	Inhibits steps in murein (peptidoglycan) biosynthesis and assembly
Polyenes	Amphotericin	Streptomyces nodosus	Fungi (Histoplasma)	Inactivate membranes containing sterols
	Nystatin	Streptomyces noursei	Fungi (Candida)	Inactivate membranes containing sterols
Rifamycins	Rifampicin	Streptomyces mediterranei	Gram-positive and Gram-negative bacteria,Mycobacterium tuberculosis	Inhibits transcription (bacterial RNA polymerase)
Tetracyclines	Tetracycline	Streptomycesspecies	Gram-positive and Gram-negative bacteria, Rickettsias	Inhibit translation (protein synthesis)
Semisynthetic tetracycline	Doxycycline		Gram-positive and Gram-negative bacteria, RickettsiasEhrlichia,Borrelia	Inhibit translation (protein synthesis)
Chloramphenicol	Chloramphenicol	Streptomyces venezuelae	Gram-positive and Gram-negative bacteria	Inhibits translation (protein synthesis)
Quinolones	Nalidixic acid	synthetic	Mainly Gram-negative bacteria	Inhibits DNA replication
Fluoroquinolones	Ciprofloxacin	synthetic	Gram-negative and some  Gram-positive bacteria (Bacillus anthracis)	Inhibits DNA replication
Growth factor analogs	Sulfanilamide, Gantrisin, Trimethoprim	synthetic	Gram-positive and Gram-negative bacteria	Inhibits folic acid metabolism (anti-folate)
	Isoniazid (INH)	synthetic	Mycobacterium tuberculosis	Inhibits mycolic acid synthesis; analog of pyridoxine (Vit B6)
	para-aminosalicylic acid  (PAS)	synthetic	Mycobacterium tuberculosis	Anti-folate

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