Classes of Antibiotics and their PropertiesChemical class Beta-lactams (penicillins and cephalospori ns) Semisyntheti c betalactams Clavulanic Acid Examples Penicillin G, Cephalothin Ampicillin, Amoxicillin Augmentin is clavulanic Streptomyces acid plus clavuligerus Amoxicillin Biological source Penicillium notatum and Cephalosporium species Spectrum (effective against) Gram-positive bacteria Mode of action Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly

Inhibits steps in cell wall Gram-positive and Gram(peptidoglycan) synthesis and murein negative bacteria assembly Gram-positive and GramInhibitor of bacterial beta-lactamases negative bacteria

Monobactam Aztreonam s Carboxypene Imipenem ms Aminoglycosi Streptomycin des Gentamicin Glycopeptide Vancomycin s Lincomycins Clindamycin Erythromycin, Azithromycin

Macrolides

Polypeptides Polymyxin Bacitracin Polyenes Amphotericin Nystatin Rifamycins Rifampicin

Tetracyclines Tetracycline Semisyntheti Doxycycline c tetracycline Chloramphen Chlorampheni icol col Quinolones Nalidixic acid Fluoroquinolo Ciprofloxacin nes Growth factor Sulfanilamide, analogs Gantrisin, Trimethoprim

Inhibits steps in cell wall Chromobacterium Gram-positive and Gram(peptidoglycan) synthesis and murein violaceum negative bacteria assembly Inhibits steps in cell wall Streptomyces Gram-positive and Gram(peptidoglycan) synthesis and murein cattleya negative bacteria assembly Streptomyces Gram-positive and GramInhibits translation (protein synthesis) griseus negative bacteria Gram-positive and GramMicromonospora negative bacteria esp. Inhibits translation (protein synthesis) species Pseudomonas Amycolatopsis Gram-positive bacteria, Inhibits steps in murein orientalisNocardia esp. Staphylococcus (peptidoglycan) biosynthesis and orientalis (formerly aureus assembly designated) Gram-positive and GramStreptomyces negative bacteria esp. Inhibits translation (protein synthesis) lincolnensis anaerobic Bacteroides Gram-positive bacteria, Streptomyces Gram-negative bacteria Inhibit translation (protein synthesis) erythreus not enterics, Neisseria, Legionella, Mycoplasma Bacillus polymyxa Gram-negative bacteria Damages cytoplasmic membranes Inhibits steps in murein Bacillus subtilis Gram-positive bacteria (peptidoglycan) biosynthesis and assembly Streptomyces Inactivate membranes containing Fungi (Histoplasma) nodosus sterols Streptomyces Inactivate membranes containing Fungi (Candida) noursei sterols Gram-positive and GramStreptomyces negative bacteria, Inhibits transcription (bacterial RNA mediterranei Mycobacterium polymerase) tuberculosis Gram-positive and GramStreptomyces negative bacteria, Inhibit translation (protein synthesis) species Rickettsias Gram-positive and Gramnegative bacteria, Inhibit translation (protein synthesis) Rickettsias Ehrlichia, Borrelia Streptomyces Gram-positive and GramInhibits translation (protein synthesis) venezuelae negative bacteria synthetic Mainly Gram-negative Inhibits DNA bacteria replication synthetic Gram-negative and Inhibits DNA replication some Gram-positive bacteria (Bacillus anthracis) synthetic Gram-positive and Gram- Inhibits folic acid metabolism (antinegative bacteria folate)

Isoniazid (INH) synthetic parasynthetic aminosalicylic acid (PAS)

Mycobacterium tuberculosis Mycobacterium tuberculosis

Inhibits mycolic acid synthesis; analog of pyridoxine (Vit B6) Anti-folate

Cell wall synthesis inhibitors Cell wall synthesis inhibitors generally inhibit some step in the synthesis of bacterial peptidoglycan. They exert their selective toxicity against bacteria because humans cells lack cell walls. Beta lactam antibiotics. Chemically, these antibiotics contain a 4-membered beta lactam ring. They are the products of two genera of fungi, Penicillium and Cephalosporium, and are correspondingly represented by the penicillins and cephalosporins. Chemical structures of some beta-lactam antibiotics. Clockwise: penicillin, cephalosporin, monobactam, carbapenem. Note the characteristic structure of the beta lactam ring. The beta lactam antibiotics are stereochemically related to D-alanyl-D-alanine, which is a substrate for the last step in peptidoglycan synthesis, the final cross-linking between between peptide side chains. Penicillins bind to and inhibit the carboxypeptidase and transpeptidase enzymes that are required for this step in peptidoglycan biosynthesis. Beta lactam antibiotics are bactericidal and require that cells be actively growing in order to exert their toxicity. Different beta lactams differ in their spectrum of activity and their effect on Gram-negative rods, as well as their toxicity, stability in the human body, rate of clearance from blood, whether they can be taken orally, ability to cross the blood-brain barrier, and susceptibility to bacterial beta-lactamases. Natural penicillins, such as penicillin G or penicillin V (benzyl penicillin), are produced by fermentation of Penicillium chrysogenum. They are effective against streptococci, gonococci and staphylococci, except where resistance has developed. They are considered narrow spectrum since they are not effective against Gram-negative rods. Penicillin G (Benzylpenicillin) is typically given by parenteral administration because it is unstable in the acid of the stomach. However, this achieves higher tissue concentrations than orally-administered penicillins and this increases its antibacterial potential. "PenG" may be used in treatment of bacterial endocarditis, gonorrhea, syphilis, meningitis, and pneumonia. Semisynthetic penicillins first appeared in 1959. A mold produces the main part of the molecule (6aminopenicillanic acid), which can be modified chemically by the addition of side chains. Many of these compounds have been developed to have distinct benefits or advantages over penicillin G, such as increased spectrum of activity (effectiveness against Gram-negative rods), resistance to penicillinase, effectiveness when administered orally, etc.; amoxicillin and ampicillin have broadened spectra against Gram-negative bacteria and are effective orally; methicillin is penicillinase-resistant. The semisynthetic beta-lactam, amoxicillin. Amoxicillin is usually the drug of choice within the class because it is better absorbed following oral administration than other beta-lactam antibiotics. It is susceptible to degradation by bacterial beta-lactamase enzymes so it may be given with calvulanic acid (below) to decrease its susceptibility. It is used against a wide range of Gram-positive bacteria, including Streptococcus pyogenes, penicillin-sensitive Streptococcus pneumoniae, non beta-lactamase producing strains of Staphylococcus aureus and Enterococcus faecalis. Susceptible Gram-negative organisms include non betalactamase producing strains of Haemophilus influenzae, Neisseria gonorrhoeae and N. meningitidis. Clavulanic acid is a chemical sometimes added to a semisynthetic penicillin preparation. Thus, amoxicillin plus clavulanate is clavamox or augmentin. The clavulanate is not an antimicrobial agent. It inhibits beta lactamase enzymes and has given extended life to penicillinase-sensitive beta lactams. The structure of calvulanic acid. Clavulanic acid is not an antibiotic. It is a beta-lactamase inhibitor sometimes combined with semisynthetic beta lactam antibiotics to overcome resistance in bacteria that produce beta-lactamase enzymes, which otherwise inactivate the antibiotic. Most commonly it is combined with amoxicillin (above) as Augmentin (trade name) or the veterinary preparation, clavamox. Although nontoxic, penicillins occasionally cause death when administered to persons who are allergic to them. In the U.S. there are 300 - 500 deaths annually due to penicillin allergy. In allergic individuals the beta lactam molecule attaches to a serum protein and initiates an IgE-mediated inflammatory response. Cephalosporins are beta lactam antibiotics with a similar mode of action to penicillins. They are produced by species of Cephalosporium molds. The have a low toxicity and a somewhat broader spectrum than natural penicillins. They are often used as penicillin substitutes against Gram-negative bacteria and in surgical prophylaxis. They are subject to degradation by some bacterial beta-lactamases, but they tend to

be resistant to beta-lactamases from S. aureus. The core structure of cephalosporin. Substituent groups added at position X on the six-membered ring generates variants of the antibiotic. Two other classes of beta lactams are the carbapenems and monobactams. The latter are particularly useful for the treatment of allergic individuals. A person who becomes allergic to penicillin usually becomes allergic to the cephalosporins and the carbapenems as well. Such individuals can still be treated with the monobactams, which are structurally different so as not to induce allergy. Aztreonam is a synthetic monocyclic beta lactam antibiotic (a monobactam) originally isolated from the bacterium Chromobacterium violaceum. It is not useful against Gram-positive bacteria but it has strong activity against a wide range of susceptible Gram-negative bacteria, including Pseudomonas aeruginosa, E. coli, Haemophilus and Klebsiella. Bacitracin is a polypeptide antibiotic produced by Bacillus species. It prevents cell wall growth by inhibiting the release of the muropeptide subunits of peptidoglycan from the lipid carrier molecule that carries the subunit to the outside of the membrane. Teichoic acid synthesis, which requires the same carrier, is also inhibited. Bacitracin has a high toxicity which precludes its systemic use. It is present in many topical antibiotic preparations, and since it is not absorbed by the gut, it is given to "sterilize" the bowel prior to surgery. Bacitracin is a polypeptide antibiotic produced by the licheniformis group of Bacillus subtilis var. Tracy. It is effective used topically, primarily against Gram-positive bacteria. It is used in ointment or cream form for topical treatment of a variety of localized skin and eye infections, as well as for the prevention of wound infections. A popular brand name Neosporin, contains bacitracin, neomycin and polymyxin B. Cycloserine inhibits the early stages of murein synthesis where D-alanyl-D-alanine is added to the growing peptide side chain. The antibiotic resembles D-alanine in spatial structure, and it competitively inhibits the racemase reaction that converts L-alanine to D-alanine and the synthetase reaction that joins two D-alanine molecules. The affinity of cycloserine for these enzymes is about a hundred times greater than that of Dalanine. Cycloserine enters bacterial cells by means of an active transport system for glycine and can reach a relatively high intracellular concentration. This concentrating effect, along with its high affinity for susceptible enzymes, enables cycloserine to function as a very effective antimicrobial agent. However, it is fairly toxic and has limited use as a secondary drug for tuberculosis. Cycloserine is an oral broad spectrum antibiotic effective against tuberculosis, by inhibiting cell wall synthesis of TB bacilli at the early stages of peptidoglycan synthesis. For the treatment against tuberculosis, it is classified as a second line drug. Glycopeptides, such as the antibiotic vancomycin, inhibit both transglycosylation and transpeptidation reactions during peptidoglycan assembly. They bind to the muropeptide subunit as it is transferred out of the cell cytoplasm and inhibit subsequent polymerization reactions. Vancomycin is not effective against Gram-negative bacteria because it cannot penetrate their outer membrane. However, it has become important in clinical usage for treatment of infections by strains of Staphylococcus aureus that are resistant to virtually all other antibiotics (MRSA). Vancomycin is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of vancomycin-resistant organisms means that it is increasingly being displaced from this role by linezolid and the carbapenems.

Cell membrane inhibitors These antibiotics disorganize the structure or inhibit the function of bacterial membranes. The integrity of the cytoplasmic and outer membranes is vital to bacteria, and compounds that disorganize the membranes rapidly kill the cells. However, due to the similarities in phospholipids in eubacterial and eucaryotic membranes, this action is rarely specific enough to permit these compounds to be used systemically. The only antibacterial antibiotics of clinical importance that act by this mechanism are the polymyxins, produced by Bacillus polymyxa. Polymyxin is effective mainly against Gram-negative bacteria and is usually limited to topical usage. Polymyxins bind to membrane phospholipids and thereby interfere with membrane function. Polymyxin is occasionally given for urinary tract infections caused by Pseudomonas strains that are gentamicin, carbenicillin and tobramycin resistant. The balance between effectiveness and damage to the kidney and other organs is dangerously close, and the drug should only be given under close supervision in the hospital. Polymyxin B. Polymyxins are cationic detergent antibiotics, with a general structure of a cyclic peptide with

a long hydrophobic tail. They disrupt the structure of the bacterial cell membrane by interacting with its phospholipids. Polymyxins have a bactericidal effect on Gram-negative bacilli, especially on Pseudomonas and coliform bacteria. Polymyxin antibiotics are highly neurotoxic and nephrotoxic, and very poorly absorbed from the gastrointestinal tract. Polymyxins also have antifungal activity.

Protein synthesis inhibitors Many therapeutically useful antibiotics owe their action to inhibition of some step in the complex process of protein synthesis. Their attack is always at one of the events occurring on the ribosome and never at the stage of amino acid activation or attachment to a particular tRNA. Most have an affinity or specificity for 70S (as opposed to 80S) ribosomes, and they achieve their selective toxicity in this manner. The most important antibiotics with this mode of action are the tetracyclines, chloramphenicol, the macrolides (e.g. erythromycin) and the aminoglycosides (e.g. streptomycin). The aminoglycosides are products of Streptomyces species and are represented by streptomycin, kanamycin, tobramycin and gentamicin. These antibiotics exert their activity by binding to bacterial ribosomes and preventing the initiation of protein synthesis. Streptomycin binds to 30S subunit of the bacterial ribosome, specifically to the S12 protein which is involved in the initiation of protein synthesis. Experimentally, streptomycin has been shown to prevent the initiation of protein synthesis by blocking the binding of initiator N-formylmethionine tRNA to the ribosome. It also prevents the normal dissociation of ribosomes into their subunits, leaving them mainly in their 70S form and preventing the formation of polysomes. The overall effect of streptomycin seems to be one of distorting the ribosome so that it no longer can carry out its normal functions. This evidently accounts for its antibacterial activity but does not explain its bactericidal effects, which distinguishes streptomycin and other aminoglycosides from most other protein synthesis inhibitors. Streptomycin is the first aminoglycoside antibiotic to be discovered, and was the first antibiotic to be used in treatment of tuberculosis. It was discovered in 1943, in the laboratory of Selman Waksman at Rutgers University. Waksman and his laboratory discovered several antibiotics, including actinomycin, streptomycin, and neomycin. Streptomycin is derived from the bacterium, Streptomyces griseus. Streptomycin stops bacterial growth by inhibiting protein synthesis. Specifically, it binds to the 16S rRNA of the bacterial ribosome, interfering with the binding of formyl-methionyl-tRNA to the 30S subunit. This prevents initiation of protein synthesis. Kanamycin and tobramycin have been reported to bind to the ribosomal 30S subunit and to prevent it from joining to the 50S subunit during protein synthesis. They may have a bactericidal effect because this leads to cytoplasmic accumulation of dissociated 30S subunits, which is apparently lethal to the cells. Aminoglycosides have been used against a wide variety of bacterial infections caused by Gram-positive and Gram-negative bacteria. Streptomycin has been used extensively as a primary drug in the treatment of tuberculosis. Gentamicin is active against many strains of Gram-positive and Gram-negative bacteria, including some strains of Pseudomonas aeruginosa. Kanamycin is active at low concentrations against many Gram-positive bacteria, including penicillin-resistant staphylococci. Gentamicin and Tobramycin are mainstays for treatment of Pseudomonas infections. An unfortunate side effect of aminoglycosides has tended to restrict their usage: prolonged use is known to impair kidney function and cause damage to the auditory nerves leading to deafness. Gentamicin is an aminoglycoside antibiotic, used mostly to treat Gram-negative infections. However, it is not used for Neisseria gonorrhoeae, Neisseria meningitidis or Legionella pneumophila infections. It is synthesized by Micromonospora, a genus of Gram-positive bacteria widely distributed in water and soil. Like all aminoglycosides, when gentamicin is given orally, it is not systemically active because it is not absorbed to any appreciable extent from the small intestine. It is useful in treatment of infections caused by Pseudomonas aeruginosa. The tetracyclines consist of eight related antibiotics which are all natural products of Streptomyces, although some can now be produced semisynthetically or synthetically. Tetracycline, chlortetracycline and doxycycline are the best known. The tetracyclines are broad-spectrum antibiotics with a wide range of activity against both Gram-positive and Gram-negative bacteria. Pseudomonas aeruginosa is less sensitive but is generally susceptible to tetracycline concentrations that are obtainable in the bladder. The tetracyclines act by blocking the binding of aminoacyl tRNA to the A site on the ribosome. Tetracyclines inhibit protein synthesis on isolated 70S or 80S (eucaryotic) ribosomes, and in both cases, their effect is on the small ribosomal subunit. However, most bacteria possess an active transport system for tetracycline that will allow intracellular accumulation of the antibiotic at concentrations 50 times as great as that in the medium. This greatly enhances its antibacterial effectiveness and accounts for its specificity of action, since an effective concentration cannot be accumulated in animal cells. Thus a blood level of tetracycline which is

harmless to animal tissues can halt protein synthesis in invading bacteria. The tetracyclines have a remarkably low toxicity and minimal side effects when taken by animals. The combination of their broad spectrum and low toxicity has led to their overuse and misuse by the medical community and the wide-spread development of resistance has reduced their effectiveness. Nonetheless, tetracyclines still have some important uses, such as the use of doxycycline in the treatment of Lyme disease. Some newly discovered members of the tetracycline family (e.g. chelocardin) have been shown to act by inserting into the bacterial membrane, not by inhibiting protein synthesis. The tetracycline core structure. The tetracyclines are a large family of antibiotics that were discovered as natural products of Streptomyces bacteria beginning in the late 1940s. Tetracycline sparked the development of many chemically altered antibiotics and in doing so has proved to be one of the most important discoveries made in the field of antibiotics. It is a classic "broad-spectrum antibiotic" used to treat infections caused by Gram-positive and Gram-negative bacteria and some protozoa. Doxycycline is a semisynthetic tetracycline developed in the 1960s. It is frequently used to treat chronic prostatitis, sinusitis, syphilis, chlamydia, pelvic inflammatory disease, acne and rosacea. In addition, it is used in the treatment and prophylaxis of anthrax and in prophylaxis against malaria. It is also effective against Yersinia pestis (the infectious agent of bubonic plague) and is prescribed for the treatment of Lyme disease, ehrlichiosis and Rocky Mountain spotted fever. Because doxycycline is one of the few medications that is effective in treating Rocky Mountain spotted fever (with the next best alternative being chloramphenicol), it is indicated even for use in children for this illness. Chloramphenicol is a protein synthesis inhibitor that has a broad spectrum of activity but it exerts a bacteriostatic effect. It is effective against intracellular parasites such as the rickettsiae. Unfortunately, aplastic anemia develops in a small proportion (1/50,000) of patients. Chloramphenicol was originally discovered and purified from the fermentation of a Streptomyces species, but currently it is produced entirely by chemical synthesis. Chloramphenicol inhibits the bacterial enzyme peptidyl transferase, thereby preventing the growth of the polypeptide chain during protein synthesis. Chemical structure of chloramphenicol Chloramphenicol is entirely selective for 70S ribosomes and does not affect 80S ribosomes. Its unfortunate toxicity towards the small proportion of patients who receive it is in no way related to its effect on bacterial protein synthesis. However, since mitochondria originated from procaryotic cells and have 70S ribosomes, they are subject to inhibition by some of the protein synthesis inhibitors including chloramphenicol. This likely explains the toxicity of chloramphenicol. The eucaryotic cells most likely to be inhibited by chloramphenicol are those undergoing rapid multiplication, thereby rapidly synthesizing mitochondria. Such cells include the blood forming cells of the bone marrow, the inhibition of which could present as aplastic anemia. Chloramphenicol was once a highly prescribed antibiotic and a number of deaths from anemia occurred before its use was curtailed. Now it is seldom used in human medicine except in life-threatening situations (e.g. typhoid fever). The macrolide family of antibiotics is characterized by structures that contain large lactone rings linked through glycoside bonds with amino sugars. The most important members of the group are erythromycin and oleandomycin. Erythromycin is active against most Gram-positive bacteria, Neisseria, Legionella and Haemophilus, but not against the Enterobacteriaceae. Macrolides inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit. Binding inhibits elongation of the protein by peptidyl transferase or prevents translocation of the ribosome or both. Macrolides are bacteriostatic for most bacteria but are cidal for a few Gram-positive bacteria. Chemical structure of a macrolide antibiotic, erythromycin. Azithromycin, shown above, is a subclass of macrolide antibiotics. Azithromycin is one of the world's bestselling antibiotics. It is s derived from erythromycin, but it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring, thus making the lactone ring 15membered. Azithromycin is used to treat certain bacterial infections, most often bacteria causing middle ear infections, tonsillitis, throat infections, laryngitis, bronchitis, pneumonia and sinusitis. It is also effective against certain sexually transmitted diseases, such as non-gonococcal urethritis and cervicitis. Lincomycin and clindamycin are a miscellaneous group of protein synthesis inhibitors with activity similar to the macrolides. Lincomycin has activity against Gram-positive bacteria and some Gram-negative bacteria (Neisseria, H. influenzae). Clindamycin is a derivative of lincomycin with the same range of antimicrobial activity, but it is considered more effective. It is frequently used as a penicillin substitute and is effective against Gram-negative anaerobes (e.g. Bacteroides). Clindamycin is a lincosamide antibiotic. It is usually used to treat infections with anaerobic bacteria but can

also be used to treat some protozoal diseases, such as malaria. It is a common topical treatment for acne, and can be useful against some methicillin-resistant Staphylococcus aureus (MRSA) infections. The most severe common adverse effect of clindamycin is Clostridium difficile-associated diarrhea (the most frequent cause of pseudomembranous colitis). Although this side-effect occurs with almost all antibiotics, including beta-lactam antibiotics, it is classically linked to clindamycin use. Effects on Nucleic Acids Some antibiotics and chemotherapeutic agents affect the synthesis of DNA or RNA, or can bind to DNA or RNA so that their messages cannot be read. Either case, of course, can block the growth of cells. The majority of these drugs are unselective, however, and affect animal cells and bacterial cells alike and therefore have no therapeutic application. Two nucleic acid synthesis inhibitors which have selective activity against procaryotes and some medical utility are the quinolones and rifamycins. Nalidixic acid is a synthetic chemotherapeutic agent that has activity mainly against Gram-negative bacteria. Nalidixic acid belongs to a group of compounds called quinolones. Nalidixic acid is a bactericidal agent that binds to the DNA gyrase enzyme (topoisomerase) which is essential for DNA replication and allows supercoils to be relaxed and reformed. Binding of the drug inhibits DNA gyrase activity. Some quinolones penetrate macrophages and neutrophils better than most antibiotics and are thus useful in treatment of infections caused by intracellular parasites. However, the main use of nalidixic acid is in treatment of lower urinary tract infections (UTI). The compound is unusual in that it is effective against several types of Gram-negative bacteria such as E. coli, Enterobacter aerogenes, K. pneumoniae and Proteus species which are common causes of UTIs. It is not usually effective against Pseudomonas aeruginosa, and Gram-positive bacteria may be resistant. Some quinolones have a broadened spectrum against Gram-positive bacteria. The fluoroquinolone, Cipro. (ciprofloxacin) was recently touted as the drug of choice for treatment and prophylaxis of anthrax, which is caused by a Gram-positive bacillus, Bacillus anthracis. Ciprofloxacin (cipro), a fluoroquinolone is a broad-spectrum antimicrobial agent that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, which is an enzyme necessary to separate replicated DNA, and thereby inhibits cell division. The rifamycins are a comparatively new group of antibiotics, also the products of Streptomyces species. Rifampicin is a semisynthetic derivative of rifamycin that is active against Gram-positive bacteria (including Mycobacterium tuberculosis) and some Gram-negative bacteria. Rifampicin acts quite specifically on the bacterial RNA polymerase and is inactive towards DNA polymerase or RNA polymerase from animal cells. The antibiotic binds to the beta subunit of the polymerase and apparently blocks the entry of the first nucleotide which is necessary to activate the polymerase, thereby blocking mRNA synthesis. It has been found to have greater bactericidal effect against M. tuberculosis than other anti-tuberculosis drugs, and it has largely replaced isoniazid as one of the front-line drugs used to treat the disease, especially when isoniazid resistance is indicated. It is effective orally and penetrates the cerebrospinal fluid so it is useful for treatment of bacterial meningitis. Rifampicin (or rifampin) is a bactericidal antibiotic from the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica (formerly known as Amycolatopsis mediterranei and Streptomyces mediterranei). Rifampicin is typically used to treat Mycobacterium infections, including tuberculosis and leprosy; and also has a role in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) in combination with fusidic acid. It is used in prophylactic therapy against Neisseria meningitidis (meningococcal) infection. It is also used to treat infection by Listeria monocytogenes, Neisseria gonorrhoeae, Haemophilus influenzae and Legionella pneumophila.

Competitive Inhibitors Many of the synthetic chemotherapeutic agents (synthetic antibiotics) are competitive inhibitors of essential metabolites or growth factors that are needed in bacterial metabolism. Hence, these types of antimicrobial agents are sometimes referred to as anti-metabolites or growth factor analogs, since they are designed to specifically inhibit an essential metabolic pathway in the bacterial pathogen. At a chemical level, competitive inhibitors are structurally similar to a bacterial growth factor or metabolite, but they do not fulfill their metabolic function in the cell. Some are bacteriostatic and some are bactericidal. Their selective toxicity is based on the premise that the bacterial pathway does not occur in the host. Sulfonamides were introduced as chemotherapeutic agents by Domagk in 1935, who showed that one of these compounds (prontosil) had the effect of curing mice with infections caused by beta-hemolytic streptococci. Chemical modifications of the compound sulfanilamide gave rise to compounds with even

higher and broader antibacterial activity. The resulting sulfonamides have broadly similar antibacterial activity, but differ widely in their pharmacological actions. Bacteria which are almost always sensitive to the sulfonamides include Streptococcus pneumoniae, beta-hemolytic streptococci and E. coli. The sulfonamides have been extremely useful in the treatment of uncomplicated UTI caused by E. coli, and in the treatment of meningococcal meningitis (because they cross the blood-brain barrier). The sulfonamides (e.g. Gantrisin and Trimethoprim) are inhibitors of the bacterial enzymes required for the synthesis of tetrahydofolic acid (THF), the vitamin form of folic acid essential for 1-carbon transfer reactions. Sulfonamides are structurally similar to para aminobenzoic acid (PABA), the substrate for the first enzyme in the THF pathway, and they competitively inhibit that step. Trimethoprim is structurally similar to dihydrofolate (DHF) and competitively inhibits the second step in THF synthesis mediated by the DHF reductase. Animal cells do not synthesize their own folic acid but obtain it in a preformed fashion as a vitamin. Since animals do not make folic acid, they are not affected by these drugs, which achieve their selective toxicity for bacteria on this basis. The chemical structures of sulfanilamide and para-aminobenzoic acid (PABA). In bacteria, sulfanilamide acts as a competitive inhibitor of the enzyme dihydropteroate synthetase, DHPS, which catalyses the conversion of PABA to dihydropteroate, a key step in folate synthesis. Folate is necessary for the cell to synthesize nucleic acids (DNA and RNA), and in its absence, cells will be unable to divide. Hence, sulfanilamide and other sulfonamides exhibit a bacteriostatic rather than bactericidal effect. Three additional synthetic chemotherapeutic agents have been used in the treatment of tuberculosis: isoniazid (INH), para-aminosalicylic acid (PAS), and ethambutol. The usual strategy in the treatment of tuberculosis has been to administer a single antibiotic (historically streptomycin, but now, most commonly, rifampicin is given) in conjunction with INH and ethambutol. Since the tubercle bacillus rapidly develops resistance to the antibiotic, ethambutol and INH are given to prevent outgrowth of a resistant strain. It must also be pointed out that the tubercle bacillus rapidly develops resistance to ethambutol and INH if either drug is used alone. Ethambutol inhibits incorporation of mycolic acids into the mycobacterial cell wall. Isoniazid has been reported to inhibit mycolic acid synthesis in mycobacteria and since it is an analog of pyridoxine (Vitamin B6) it may inhibit pyridoxine-catalyzed reactions as well. Isoniazid is activated by a mycobacterial peroxidase enzyme and destroys several targets in the cell. PAS is an anti-folate, similar in activity to the sulfonamides. PAS was once a primary anti-tuberculosis drug, but now it is a secondary agent, having been largely replaced by ethambutol. Isoniazid is also called isonicotinyl hydrazine or INH. Isoniazid is a first-line anti-tuberculosis medication used in the prevention and treatment of tuberculosis. Isoniazid is never used on its own to treat active tuberculosis because resistance quickly develops.