ANTIBIOTICS

Antibiotic development, past and present

Antibiotic is a substance produced by one microorganism which, in low concentrations, inhibit the growth of other microorganism Antibiotics are molecules that kill, or stop the growth of, microorganisms, including both bacteria and fungi. Antibiotics that kill bacteria are called "bactericidal" Antibiotics that stop the growth of bacteria are called "bacteriostatic"

How does antibiotics work

How does antibiotics work

How does antibiotics work

How does antibiotics work

Beta Lactam

Beta Lactam
Beta-lactam antibiotics inhibit the growth of sensitive bacteria by inactivating enzymes located in the bacterial cell membrane, which are involved in the third stage of cell wall synthesis. It is during this stage that linear strands of peptidoglycan are cross-linked into a fishnet-like polymer that surrounds the bacterial cell and confers osmotic stability in the hypertonic milieu of the infected patient.

Beta Lactam
Penicillins Cephalosporins Cephamycins Carbapenems Monobactams Beta-lactamase inhibitors

Beta Lactam
MECHANISMS OF BACTERIAL RESISTANCE A. Decreased penetration to the target site

The outer membrane of Gram negative bacilli provides an efficient barrier to the penetration of beta-lactam antibiotics to their target PBPs in the bacterial plasma membrane. Beta-lactams usually must pass through the hydrophilic porin protein channels in the outer membrane of Gram negative bacilli to reach the periplasmic space and plasma membrane. The permeability barrier of the outer membrane is a major factor in the resistance of Pseudomonas aeruginosa to many beta-lactam antibiotics.

Beta Lactam
MECHANISMS OF BACTERIAL RESISTANCE B. Alteration to the Target site

The target sites for the beta-lactams are the PBPs in the cytoplasmic membrane. Alterations in PBPs may influence their binding affinity for beta-lactam antibiotics and therefore the sensitivity of the altered bacterial cell to inhibition by these antibiotics. Such a mechanism is responsible for penicillin resistance in pneumococci, methicillin (oxacillin) resistance in staphylococci, and for bacteria with increasing intrinsic resistance to beta-lactams, such as gonococci, enterococci, and Haemophilus influenzae.

Beta Lactam
MECHANISMS OF BACTERIAL RESISTANCE C. Inactivation by a bacterial enzyme

Production of beta-lactamase is the major mechanism of resistance to the beta-lactam antibiotics in clinical isolates. Such bacterial enzymes may cleave predominantly penicillins (penicillinases), cephalosporins (cephalosporinases), or both (beta-lactamases). Their production may be encoded within the bacterial chromosome (and hence be characteristic of an entire species) or the genes may be acquired on a plasmid or transposon (and hence be characteristic of an individual strain rather than the species). Bacteria may synthesize the beta-lactamase constitutively (as for many plasmid-mediated enzymes) or synthesis may be inducible in the presence of antibiotic (as for many chromosomal enzymes). Inducible beta-lactamases may not be reliably detected by initial susceptibility testing, particularly with the newer rapid methods.

Tetracyclines

Tetracyclines
Tetracyclines are polyketide antibiotics, biosynthesized in a fashion similar to that of fatty acids, erythromycin and a host of other antibiotics. Tetracyclines are produced naturally by Streptomyces aureofaciens Tetracyclines bind to the bacterial ribosome, preventing the binding of aminoacyl tRNA to the ribosomal A site. This prevents bacterial protein translation

Structure activity relationships

Tetracycline molecules comprise a linear fused tetracyclic nucleus (rings designated A, B, C, and D [Table 2]) to which a variety of functional groups are attached Features important for antibacterial activity among the tetracyclines are
maintenance of the linear fused tetracycle, naturally occurring (a) stereochemical configurations at the 4a, 12a (A-B ring junction), and 4 (dimethylamino group) positions, and conservation of the keto-enol system (positions 11, 12, and 12a) in proximity to the phenolic D ring.

It is well established that tetracyclines inhibit bacterial protein synthesis by preventing the association of aminoacyltRNA with the bacterial ribosome (44, 263). Therefore, to interact with their targets these molecules need to traverse one or more membrane systems depending on whether the susceptible organism is gram positive or gram negative. Hence, a discussion of the mode of action of tetracyclines requires consideration of uptake and ribosomal binding mechanisms.

Macrolide and ketolides

Macrolide and ketolides

erythromycin is effective for the treatment of infections caused by some intracellular pathogens, including species of Legionella,Mycoplasma, and Chlamydia. Several drawbacks, however, have limited the use of erythromycin, including frequent gastrointestinal intolerance and a short serum half-life.

Erythromycin
macrolide antibiotic whose structure consists of a macrocyclic 14-membered lactone ring attached to two sugar moieties (a neutral sugar, cladinose, and an amino sugar, desosamine). In the acidic environment of the stomach, it is rapidly degraded to the 8,9-anhydro-6,9- hemiketal and then to the 6,9,9,12-spiroketal form. The hemiketal intermediate may be responsible for the gastrointestinal adverse effects associated with erythromycin [1].

Clarithromycin (6-O-methylerythromycin)
synthesized by substituting a methoxy group for the C-6 hydroxyl group of erythromycin. This substitution creates a more acid-stable antimicrobial and prevents the degradation of the erythromycin base to the hemiketal intermediate. The increased acid stability of clarithromycin results in improved oral bioavailability and reduced gastrointestinal intolerance.

Azithromycin (9-deoxo-9a-aza-9a-methyl-9ahomoerythromycin)
formed by inserting a methyl-substituted nitrogen in place of the carbonyl group at the 9a position of the aglycone ring. The resulting dibasic 15-membered ring macrolide derivative is more appropriately referred to as an azalide. This structural change makes the compound more stable in acid, significantly increases the serum half-life and tissue penetration, and results in increased activity against gramnegative organisms and decreased activity against some gram-positive organisms when compared with erythromycin

Ketolides
a new group of 14-membered macrolides, are synthesized by substituting a keto function for the a-L-cladinose moiety at position 3 of the 14-membered erythronolide A ring [4]. This change promotes greater acid stability and prevents induction of macrolide-lincosamide-streptogramin B resistance [5].

Mechanism of action and resistance

The macrolide and ketolide antimicrobials exert their antibacterial effects by reversibly binding to the 50s subunit of the bacterial ribosome.

Macrolide resistance
streptococci principally arises from either an alteration of the drug-binding site on the ribosome by methylation (macrolidelincosamide-streptogramin B resistance) or by active drug efflux

Aminoglycoside

Aminoglycoside antibiotics
Natural aminoglycoside antibiotics share a non-sugar 2deoxystreptamine (2-DOS) scaffold connected to amino sugar substituents at the 4-, 5- and 6-positions
Aminoglycosides interfere with translational fidelity by binding to the ribosomal decoding site at an internal loop of the 16S rRNA that contains three unpaired adenine residues

Resistance
decrease of intracellular drug concentration, target site modification and enzymatic drug modification.

Quinolones

MECHANISM OF ACTION
inhibition of bacterial gyrase, an enzyme involved in DNA replication, recombination and repair.

disadvantages or side effects [1,9]

Tendonitis or tendon rupture Multiple drug interactions Not used in children Newer quinolones produce additional toxicities to the heart that were not found with the older agents Gastrointestinal effects CNS effects: Headache, dizziness, and drowsiness have been reported with all fluoroquinolones. Phototoxicity:
The degree of phototoxic potential of fluoroquinolones is as follows: lomefloxacin > sparfloxacin > ciprofloxacin > norfloxacin = ofloxacin = levofloxacin = gatifloxacin = moxifloxacin.

Musculoskeletal effects. Hepatoxicity Cardiovascular effects Hypoglycemia/Hyperglycemia Hypersensitivity

Fluoroquinolone advantages: [1]

Ease of administration Daily or twice daily dosing Excellent oral absorption Excellent tissue penetration Prolonged half-lives Significant entry into phagocytic cells Efficacy Overall safety

Bacterial Resistance
alterations in the quinolone enzymatic targets (DNA gyrase), decreased outer membrane permeability or the development of efflux mechanisms.

Cyclic Peptides

Vancomycin
glycopeptide antibiotic with high activity against Gram-positive bacteria and is particularly renowned for its activity against the feared methicillin-resistant Staphylococcus aureus (MRSA) species Amycolatopsis orientalis Vancomycin and other glycopeptides inhibit cell wall synthesis by non-covalent binding to the D-Ala-D-Ala peptide motif of the cell wall precursor lipid II [10]. Four hydrogen bonds are formed when vancomycin binds the D-AlaD-Ala motif, and all of these involve the peptide backbone

Lantibiotic: Nisin
Nisin is a peptide-based antibiotic from the lantibiotic (lanthioninecontaining antibiotic) family Lactococcus lactis used as a food preservative causes leakage of intracellular molecules from cells

Cyclosporin A
Cyclosporin was isolated from the fungus Tolypocladium inflatum. Its immunosuppressive graft rejection after transplant surgery. CsA is a cyclic undecapeptide consisting completely of hydrophobic amino acids,
major immunosuppressant drug to prevent

Lincosamides
Lincosamides are derived from an amino acid and a sulfur-containing octose, a synthetic monosaccharide containing eight carbon atoms in a molecule Streptomyces lincolnensis Resistance to lincosamides, likely due to alterations in the 50S subunit by chromosomal mutation, appears to develop slowly. Plasmid mediated resistance has been observed with Bacteroides fragilis. Cross resistance with other antimicrobials has been observed in vitro.

Oxazolidinoes

Linezolid
Inhibiting a very early step in bacterial protein synthesis

Sulfa antibiotics

ANTIVIRAL DRUGS