MARK MIGUEL P.

LATRAS, RPh
ANTIBACTERIAL ANTIBIOTICS
- Antibiotics – produced by microorganisms which has the capacity of inhibiting growth and even
destroying other microorganisms
- A substance is an antibiotic, if:
o Product of metabolism
o Synthetic analogue of a naturally-occurring antibiotic
o Antagonizes the growth or survival of one or more species of microbes
o Effective in low concentrations
- Attributes:
o Selective toxicity
o Chemically stable
o Rate of biotransformation and elimination = just right
- History
o Soybean – tx of boils and carbuncles
o Moldy cheese – tx of wounds
o Alexander Fleming – discovered Penicillin
o Florey and Chain – introduced Penicillin into therapy
o Dubos – isolated Tyrothricin (mixture of polypeptides) from Bacillus brevis
o Waksman – isolated Streptomycin from Streptomyces griseus
- Overview of Antibiotics
o Acting on the Cell Wall
 Penicillins
 B-lactamase inhibitors
 Monobactams
 Penicillins
 Cephalosporin
 Bacitracin
 Cephalosporin
 Cycloserine
 Vancomycin
o Acting on the Cell Membrane
 Amphotericin B
 Polymyxin
 Nystatin
o Acting on the Ribosomes
 Chloramphenicol
 50s
o Lincomycin
o Erythromycin
 30s
o Tetracycline
o Aminoglycosides
o Acting on the Nucleic acid
 Griseofulvin
 MARK MIGUEL P. LATRAS, RPh
 Actinomycin
o Acting on the DNA/RNA
 Mitomycin C – DNA
 Rifampin- mRNA

♠ acting on cell wall & membrane – -cidal

♠ acting on protein synthesis – -static; except aminoglycoside = -cidal

Drugs Acting on Cell Wall

 B-Lactam
 Possess the Beta lactam (a four membered cyclic amide) ring structe

 MOA: Inhibition of the biosynthesis of the dipeptidoglycan – provides strength and rigidity to
the cell wall
o They acylate a specific bacterial D-transpeptidase, thereby rendering it inactive for
its role in forming peptide cross-links of two linear peptidoglycan strands by
transpeptidation and loss of D-alanine (due to inhibited D-alanine
carboxypeptidase)
 Prone to hydrolysis
 Act on G(+), G(-) and anaerobes

 Penicillin

General structure Penam Penicillanic acid Thiazolidine ring

 Discovered by A. Fleming from Penicillium notatum, P. chrysogenum

 C3, C5, C6 = chiral
 C6 = L-configuration, alpha
 C3 = D-configuration, Beta
 Made of two amino acids
o Cysteine (S1, C5, C6, C7)
o Valine (C2, C2 dimethyl, C3, C3=O, N4)
 Very acid labile
 Dose is expressed in units – antibiotic activity of 0.6mcg USP Pen G as reference standard
 MARK MIGUEL P. LATRAS, RPh

Mechanism of resistance:
1) B-lactamases/Pencillinases/Acylase/Penicillin-inactivating enzymes
2) Decreased permeability especially G-
3) Altered PBP binding
a. PBP 1a, 1b – synthesis of peptidoglycan  (-) Increased Autolysins (enzymes that
create nicks in the cell wall for attachment of new PDG units)
b. PBP 2 – maintains shape of bacilli (rod)
c. PBP 3 – Septum formation during cell division
d. PBP 4-6 – carboxypeptidase  Hydrolysis of D-Ala-D-Ala peptide  (-) not harmful

Structure-Activity Relationships

o Acid resistance
 Presence of electron withdrawing group in the acyl sidechain
o Penicillinase-resistant penicillin
 Increasing the steric hindrance at the a-carbon of the acyl group especially quaternary
substitution
 Example: Methicillin (dimethoxy)

 Isoxazoyl penicillins – requires 3-aryl/5-aryl, 3-methyl/5-methyl for effectiveness against

Staphylococcus aureus
 Examples: Dicloxacillin
o Diclo – 2 chlorine
o Cloxa – 1 chlorine
o Oxa – no chlorine
o Extended spectrum
 Introduction of ionized/polar group into ɑ-position of side chain of benzylpenicillin confers
activity against G(-) organisms

 Example: Ampicillin (amino), Amoxicillin (amino + parahydroxy)

 Incorporation of an acidic substituent at the a-benzyl carbon of benzylpenicillin

also extends the spectrum
o Example: Carbenicillin, Ticarcillin (thienyl moiety)
 MARK MIGUEL P. LATRAS, RPh

o Acylureidopenicillin
 Urea functional group at ɑ-position
 Activity same with carbenicillin and active against Klebsiella, enterobacter, P. aeruginosa
 Examples:
 Piperacillin
 Mezlocillin – S=O
 Azlocillin

Allergy to Penicillins
- Range from skin and mucous membrane rashes, drug fever and anaphylaxis
- How?  rearrangement products of Pens (penicillenic acid) + the epsilon amino group of
Lysine = penicilloyl proteins (major antigenic determinants)

o Pen G – benzylpenicillin (IV)

 Agent of choice for the treatment of more different kinds of infection
 Absorbed poorly
 K salt = preferred for salt free diet and px w/ CHF
o Pen V – phenoxymethylpenicillin (Sumapen – oral)
o Methicillin – 2,6-dimethoxyphenylpenicillin
o Oxacillin – 5-methyl-3-phenyl-1-isoxazolylpenicillin
o Ampicillin – ɑ-aminobenzylpenicillin (IV)
o Amoxicillin – ɑ-amino-p-hydroxybenzylpenicillin

o B-lactamase inhibitors
 Used in combination with a B-lactamase sensitive penicillin in the therapy
 2 classes:
 Class I – heteroatom leaving group at C1
o Clavulanic acid, Sulbactam, Tazobactam
o Clavulanic acid
 S. clavuligeris
 Very weak, not useful as antibiotic
 Acid stable
o Clavulanic acid + amoxicillin – Co-amoxiclav (Augmentin)
o Ampicillin + sulbactam (Unasyn)
o Piperacillin + Tazobactam (Tazocin)
o Potentiation: 1+0 = >1
 Class II – no heteroatom leaving group at C1
o Carbapenems
 Broadest spectrum
 Thienamycin – S. cattleya
 Meropenem – DOC for P. aeruginosa
 MARK MIGUEL P. LATRAS, RPh
 Ertapenem – longer t ½
 Biapenem
 Imipenem-Cilastatin – DOC for Enterobacter
 Cephalosphorins

General structure Cepham 3-Cephem Dihydrothiazine

- Obtained from Cephalosporium spp.

- 2 causes of oral inactivation of Cephs:
o B-lactam is prone to hydrolysis and solvolysis
o Microbial transformation of the 3-methylacetoxy group (Cephalotin, Cephaloglycin)

 1st – All Cephs including Cefadroxil, Cefazolin

 2nd – All Cefs that do not end in –ime or –one including Loracarbef, Cefuroxime and
Cefpodoxime
 3rd – All Cefs that end in –ime or –one including Ceftibuten
 4th – Cefepime and Cefpirome

 3rd Gen and 4th gen have activity against P. aeruginosa except Cefixime and Ceftibuten

Adverse reactions:
- Mild rashes to life-threatening anaphylactic reactions
- Cross sensitivity to penicillins (very low)
- N-methyl-5-thiotetrazole moiety at C3

o Higher incidence of Hypoprothrombinemia

 Cefmetazole, Cefomandole, Ceftibuten, Cefoperazone, Moxalaxtam
o Intolerance to alcohol (accumulation of Aldehyde due to inhibition of the Aldehyde
dehydrogenase) = disulfiram-like reactions
o Cefmetazole, Cefomandole, Ceftibuten, Cefoperazone

 Monobactam
-
Developed from Sulfazecin and other monocyclic B-lactam antibiotics from SAPROPHYTIC
soil bacteria in Japan and US
Examples:
 Aztreonam – active against G(-)
 Tigemonam
 MARK MIGUEL P. LATRAS, RPh

 Bacitracin
 Isolated from Bacillus subtilis
 MOA: inhibits mucopeptide cell wall synthesis of G(+) bacteria

 Vancomycin
 from S. orientalis
 MOA: cell wall synthesis by preventing the synthesis of cell wall mucopeptide polymers
(D-Ala-D-Ala terminus of the Uridine diphosphate N-acetylmuramyl peptides)
 Tx for MRSA (slow IV push)
 Tx for pseudomembranous colitis (oral)
 to prevent redman’s syndrome give diphenhydramine before administering vancomycin

♠ Drugs acting on plasma membrane

 Polypeptides
 renally toxic, lacks systemic activity (topical)

 Gramicidin
 Isolated from B. brevis
 G(+) MOA: acts on ionophores – allows uncontrolled movement of ions across cell membrane

 Polymixin
 Isolated from B. polymyxa
 G(-)

 Colistin
 Aerobacillus colistinus

♠ Drugs acting on protein synthesis – 30s (tRNA to the mRNA-Ribo)

 Tetracycline
Octahydronapthacene = 4-annulated, 6-membered ring

 Obtained from fermentation procedures from Streptomyces

 Amphoteric
 In neutral solutions = Zwitterions
 MARK MIGUEL P. LATRAS, RPh
 Forms stable complex with Ca, Mg, Fe
 Not taken with milk, antacids, iron salts
 Forms a TETRACYCLINE-CALCIUM ORTHOPHOSPATE complexes  Yellow
discoloration that darkens via photochemical reaction
 Excreted renally
 Antagonistic with penicillin

Structure Activity Relationships

- Enolized tricarbonylmethane system at C1 to C3 must be intact for good activity

- Replacement of the amide at C2 with other fxns reduces or abolishes the activity
- Monoalkylation of the amide N reduces activity in proportion to the size of the alkyl group

 Phototoxic (demeclocycline), hepatotoxic

 Doxycycline – prophylaxis for leptospirosis
 Minocycline – most potent; DOC for cholera
 Aureomycin/Chlortetracycline – S. aureofaciens
 Oxytetracycline – S. rimosus

 Aminoglycosides
Highly-substituted 1,3-diaminocyclohexane

Kanamycin, Neomycin, Gentamicin, Tobramycin – deoxystreptamine

Streptomycin - Streptadine

 So named because it consists of amino sugars linked glycosidically

 Nephrotoxic and ototoxic
 Effective against G(-) aerobic
 “mycin” – derived from streptomyces
 “micin” – derived from micromonospora
Structure Activity Relationships

- Ring 1 = responsible for the broad spectrum antibiotic, subject to bacterial inactivating
enzymes
- Ring 2 (deoxystreptamine) = few modifications possible without loss of activity
- Ring 3 = fxn groups are less sensitive to structural changes
 MARK MIGUEL P. LATRAS, RPh

Mechanisms of Resistance:
- Aminoacyltransferase (AAC)
o Acetylate
 3 NH2 - 1
 2’ NH2 - 2
 6’ NH2 - 2
- Phosphotransferases (APH)
o Phosphorylate
 3’ OH - I
 2’’ OH - III
- Nucleotidyltransferases (ANT)
o Adenylate
 4’ OH - I
 2’’ OH -III
 4’’ OH – III

 Streptomycin – 1st aminoglycoside used

 Hydrolysis yields: Streptidine and Streptobiosamine
 Streptomycin A = streptomycin
 Streptomycin B = mannisidostreptomycin
 Effective against tubercle bacilli
 Agent of choice for “occupational” bacterial infections (Tularemia, brucellosis, bubonic
plague, glanders)

 Amikacin – semisynthetic derivative of kanamycin

 Neomycin – nephrotoxic, topical
 Spectinomycin – alternative for gonorrhea for penicillin-allergic patients
 Netilmicin – ethylated Sisomicin

Sources:
Kanamycin – S. kanamyceticus
Spectinomycin- S. spectabilis
Neomycin / Mycifradin neobiotic – S. fradiae
Tobramycin – S. tenebrarius
Sisomicin – Micromonospora inyoensis
Gentamicin – Micromonospora purpurea

Acting on the 50s ribosomal subunit (translocation)

 Lincosamides/Lincomycins
 Sulfur-containing
 Isolated from S. lincolensis
 Clindamycin (Dalacin-C)
 MARK MIGUEL P. LATRAS, RPh
o Tx of acne
o DOC for endocarditis
o Prophylaxis for patients with valvular heart disease undergoing dental procedure
o Adv. effect: pseudomembranous colitis

 Macrolides
 3 common characteristics:
o Large lactone ring
o Ketone group
o Glycosidically linked amino sugar
Mechanisms of Resistance:
- Inability of the antibiotic to penetrate the cell walls of these microbes
- Production of enzymes that methylate a specific adenine residue at the erythromycin binding
site of the bacterial 50s

 Erythromycin
o Isolated from S. erythreus
o DOC for legionnaire’s disease and diphtheria
o Effective against venereal diseases
o Effective for Eaton agent pneumonia (Mycoplasma pneumoniae) and bacterial
enteritis caused by Camphylobacter jejuni and Legionnaire’s disease
o Commercial product: Erythromycin A
o Adv. effects: GI discomfort, acute cholestatic hepatitis
 Clarithromycin
o Good oral absorption
o Given with meals
o Longer t½
 Azithromycin
o Prototype Azalide (15 membered ring macrolides)
o Once a day dosing for 3 days
o Causes ototoxicity

 Oxazolidinediones
 Linezolid
o For G(+), MRSA, VRSA, VR-enterobacterfaecium

 Streptogramins
 Dalfopristin and Quinupristin
o For G(+) cocci, MRSA and life-threatening infections

 Chloramphenicol
 MARK MIGUEL P. LATRAS, RPh
 Isolated from S. venezuelae
 Very bitter taste
 Resistance: Production of Chloramphenicol acetyltransferase
 For uncomplicated typhoid fever and meningitis
 Treatment for Rickettsial infections (Rocky Mountain Spotted Fever)
 Adv. effects: gray baby syndrome, aplastic anemia

♠ Drugs acting on Nucleic Acid transcription - Synthetic

 Quinolones
 MOA: inhibition of DNA gyrase (topoisomerase II)
 DOC for UTI
 G(-) infections
 Patterned after nalidixic acid
 Excellent chelator, should not be used with antacids
 SAR:
o 1,4-dihydro-4-oxo-3-pyridine carboxylic acid – essential for antibacterial property
o Fluorine at position 6 – enhance G(+) activity
 Ex. ciprofloxacin, ofloxacin
o Piperazinyl substitution at position 7 – activity against pseudomonas
o Phototoxicity – halogen at position 8

 Rifampicin

 Nitroimidazole and Nitrofurantoin

 Nitrofurazone – tx of burns
 Furazolidone – tx of diarrhea
 Nitrofurantoin
 Nifurtimox – tx of trypanosoma cruzi
 Metronidazole
 DOC for protozoans
o Amoebiasis – caused by E. histolytica
o Giardiasis – caused by Giardia lamblia
o Gastric ulcers – caused by H. pylori
 Adv. effects: metallic taste, enzyme inhibitor, causes disulfiram effect

♠ Drugs acting on PABA synthesis

 Sulfonamides
 Discovered by Domagk from Prontosil (azo dye) → sulfanilamide
 Adv. effects:
 Crystal formation in kidneys – drink lots of H2O
 MARK MIGUEL P. LATRAS, RPh
 Causes SJS
 Kernicterus – mental retardation, jaundice
 w/ Folate reductase inhibitors
 Trimetophrim + sulfamethoxazole – Cotrimoxazole (Bactrim)
 Pyrimethamine + sulfadoxine (Fansidar)
 Use:
 DOC in the treatment and prophylaxis in P. jiroveci
 1st line for UTI
 Burn – mafenide, Ag sulfadiazine
 Resistant malaria – Fansidar
 Conjunctivitis and ocular infections – Na sulfacetamide

Pathway:

Guanosine Pteridine diphosphate + PABA [Dihydropteroate synthetase (-)

Sulfonamides)]Dihydropteroic acidDihydrofolic acid[Dihydrofolate Reductase (-) Trimethoprim)]
 Tetrahydrofolic acid  Folinic acid/Leucovorin

 Sulfone
 Inhibition of fatty acid synthesis
 Dapsone