ANTIBACTERIALS II

Miss H Parkar (hafiza.parkar@up.ac.za)

Antibacterial Therapy
• Exploits differences between bacteria and host
• Divided into 5 broad classes based on their MOA:
1. Cell wall synthesis inhibitors
2. Inhibitors of cell membrane%%function
3. Inhibitors of metabolism
4. Protein synthesis inhibitors
5. Inhibitors of nucleic acid function or synthesis
%%
1. Inhibitors of Cell Wall Synthesis
1. Beta-lactam antibiotics:
• Penicillins
• Cephalosporins
• Carbapenems
• Monobactam %%
2. Beta-lactamase inhibitors:
• Clavulanic acid
• Sulbactam
• Tazobactum
3. Other:
• Vancomycin
• Daptomycin
• Telavancin
Bacterial Cell Wall Synthesis
• Bacterial cell wall composed of multiple layers of peptidoglycan
 Peptidoglycan not found in host cells
• Each layer consists of multiple backbones of amino sugars –
alternating N-acetylglucosamine (NAG) and N-acetylmuramic acid
(NAM) residues
• NAM contains short peptide side-chains that are cross-linked to
form a polymeric lattice
Bacterial Cell Wall Synthesis
1. Bacterial cell wall consists of strands of
repeating N-acetylglucosamine (NAG)
and N-acetylmuramic acid (NAM)
subunits

2. PBP binds peptide side chains and forms

the cross-link with the expulsion of one
D-Alanine from one peptide side chain

3. PBP dissociates from the wall once the

cross-link has been formed

4. If penicillin is added to the system. It

enters the active site of the PBP and
reacts with the serine group

5. The beta-lactam ring of penicillin is

irreversibly opened permanently blocking
the active site
Inhibitors of cell wall synthesis
• Penicillin and other cell wall synthesis inhibitors prevent the
synthesis of intact peptidoglycan
• Interfere with last step of bacterial cell wall synthesis
(transpeptidation or cross-linkage)
• Cell wall is weakened leading to%% cell lysis
• Target synthesis process
• Only affect rapidly growing cells
β-lactams
• Contain β-lactam ring
• MOA:
• Bind penicillin binding proteins (PBP)
• Cell membrane proteins involved in cell wall synthesis
• Inhibit final polymerization of peptidoglycan synthesis
• Transpeptidation reaction
• Responsible for cross-linking carbohydrate chains
• Disrupted cell wall synthesis
• Cell lysis via osmotic pressure or autolysin activation
• Resistance: via β-lactamases (hydrolyses cyclic amide
bond of β-lactam ring), altered PBP and poor
penetration
β-lactamase Enzyme
 Penicillins are synergistic

β-lactams: Penicillins with aminoglycosides

• Group of over 50 chemically related antibiotics

• Differ in R-substituent on 6-aminopenicillanic acid
residue
• Antibacterial spectrum dependent on
• Ability to cross peptidoglycan cell wall
• Size, charge and hydrophobicity
• Most widely effective and least toxic
• Limited by resistance
β-lactams: Penicillins
• MOA:
• Bind PBP’s
• Interfere with the last step of bacterial cell wall synthesis
(transpeptidation or cross-linkage)
• Results in exposure of the osmotically less stable membrane
• Cell lysis then occurs through osmotic pressure or activation of
autolysins
• Bactericidal
• Work in a time-dependent fashion
β-lactams: Penicillins
• Natural penicillins
• Fermentation of Penicillium chrysogenum
• Penicillin G and Penicillin V
• Acid labile versus acid stable
• Narrow spectrum of activity
• β-lactamase (Penicillinase) sensitive
• β-lactamase can be constitutive or acquired via plasmid transfer
• Effective against gram-positive cocci and spirochetes (Treponema
pallidium)
β-lactams: Penicillins
• Broad spectrum penicillins Absorption of
penicillinase-
• Ampicillin and amoxicillin resistant penicillin
• Semisynthetic: R-groups added decreased by food
• Similar spectrum to natural penicillins
• More effective against gram (-) bacilli
• Formulations with β-lactamase inhibitors extend spectrum
• Covalently bind with β-lactamase enzymes
• Clavulanic acid and sulbactram
• Extended spectrum penicillins
• Carbenicillin, ticarcillin, piperacillin
• Activity against Pseudomonas aeruginosa
β-lactamase Inhibitors
• Hydrolysis of β-lactam ring destroys activity
• Enzymatic cleavage or acid
• Clavulanic acid, sulbactam, tazobactam
• Contain β-lactam ring
• Bind to and inactivate β-lactamases
• No significant antibacterial activity alone
• Used in combination formulations
β-lactams: MRSA
• Methicillin resistant Staphylococcus aureus
• Source of serious community and nosocomial (hospital-acquired)
infections
• Resistant to most commercially available β-lactam antibiotics
• MRSA infections may affect :
• Bloodstream
• Lungs
• Heart
• Bones
• Joints
 Penicillin's cross the placental
β-lactams: Penicillins barrier, but none have been
shown to be teratogenic

• Adverse effects
• Hypersensitivity reactions (~5% of patients)
• Degradation products (penicilloic acid) combine with host protein,
become antigenic and induce immune reaction
• Cation toxicity: sodium or potassium salts
• Diarrhoea
• Nephritis
• Neurotoxicity
• Hematological toxicity
• Decreased coagulation
β-lactams: Cephalosporins
• Produced semi-synthetically General poor oral
absorption
• Attachment of side chains to 7-aminocephalosporanic acid Well distributed in
• Classified as 1st, 2nd, 3rd and 4th generation fluids
• Based on bacterial susceptibility and β-lactamase resistance
• Generally
• Spectrum against gram (-) increase with ascending generation
• Spectrum against gram (+) decrease with ascending
generation
• Cefepime: 4th generation, wide spectrum
• Therapeutic levels in CSF
• Third generation cephalosporins
β-lactams: Cephalosporins
• Advanced generation cephalosporins:
• Ceftaroline: IV prodrug
• Broadspectrum: Gram- positive and negative
• Importantly also, P. aeruginosa, extended spectrum, β-lactamase (ESBL)-producing
Enterobacteriaceae, and Acinetobacter baumannii
• MOA:
• Unique structure binds to PBP2a found with MRSA and PBP2x found with
Streptococcus pneumoniae

It is the only commercially

available β-lactam in the US with
activity against MRSA
β-lactams: Carbapenems
• Based on β-lactam structure
• Sulfur of thiazolidine ring externalized, replaced by carbon
• Imipenem, meropenem
• Imipenem compounded with cilastatin
• Protect from metabolism by renal dehydropeptidase
• Broadest spectrum β-lactam
• High levels of imipenem may provoke seizures
β-lactams: Monobactams
• Based on β-lactam structure
• β-lactam structure ring is not fused to another
• Aztreonam
• Narrow antimicrobial spectrum
• Antimicrobial activity directed primarily against gram-negative pathogens
• Treatment of septicaemia and complicated UTI’s
Vancomycin Telavancin: synthetic
derivative of vancomycin
• Tricyclic glycopeptide
• Inhibit cell wall phospholipid synthesis and transglycosylation
• Not inactivated by β-lactamases
• Primarily effective against gram (+) organisms
• Effective against multi-drug resistant organisms (MRSA and MRSE)
• Restrict use to serious infections
• Synergism with aminoglycosides
• Flushing (‘red man syndrome’)
• Histamine release following infusion
• Pre-treat with anti-histamine or slow infusion rate
Other cell wall inhibitors
• Daptomycin
• Bactericidal concentration-dependent cyclic lipopeptide antibiotic
• Telavancin
• Bactericidal concentration-dependent semisynthetic lipoglycopeptide
antibiotic
• Fosfomycin
• Bactericidal synthetic derivative of phosphonic acid
• Inhibiting enzymes which catalyze the first step in peptidoglycan synthesis
2. Inhibitors of cell membrane function
1. Isoniazid
2. Polymixins
3. Polyenes (Amphotericin )
%%
Isoniazid
• Synthetic pyridoxine analogue
• Pro-drug activated by mycobacterial catalase-peroxidase
• Competitive inhibitor of bacterial fatty acid synthase II
• Enzyme involved in synthesis of mycolic acid
• INH undergoes metabolism in the liver by N-acetylation
• Genetic control of acetylation: slow and fast acetylators
Adverse effects Neurotoxicity: pyridoxine
(vitamin B6) deficiency
• Hepatotoxic: jaundice, hepatitis
• Neurotoxic: peripheral neuritis, restlessness, twitching, insomnia
Polymixin
• Cation polypeptides bind to cell membrane phospholipids
• Detergent-like effect that disrupts cell membrane integrity
• Leakage of cellular components and cell death
• Polymyxin B and colistin (polymyxin E)
• Concentration-dependent bactericidal agents
• Intrinsic resistance
• Altered cell membrane lipid polysaccharides
• Limited use due to risk of nephrotoxicity and neurotoxicity

Common use as salvage therapy

3. Inhibitors of metabolism
Folate inhibitors (antagonists):
1. Sulphonamides
2. Trimethoprim
Folate inhibitors
• Enzymes require folate-derived co-factors
• Synthesis of purines and pyrimidines
• Precursors of DNA and RNA
• Humans require folate in the form of dietary folic acid
• Synthesis of tetrahydrofolic acid
• Bacteria are mostly impermeable to folic acid
• Require de novo synthesis
• Inhibited by sulphonamides and folate antagonists
• Useful in combination
Folate Inhibitors
Pteridine precursors
+
P-Aminobenzoid acid (PABA)

Dihydropteroate
Sulfonamides
synthase

Dihydrofolic acid

Dihydrofolate
Trimethoprim Co-trimoxazole:
reductase
sulphamethoxazole and
Tetrahydrofolic acid trimethoprim
Sulfonamides
• Dihydrofolic acid synthesized from
• p-amino-benzoic acid (PABA), pteridine and glutamate
• Sulfonamides are synthetic analogues of PABA
• Competitive substrate for dihydropteroate synthase
• Bacteriostatic in organisms requiring de novo folate synthesis
• pKa dependent binding to serum albumin
• Short-acting: sulfadimidine
• Intermediate-acting: sulfamethoxazole
• Long-acting: sulfametopyrazone
Sulfonamides
Adverse effects
• Crystalluria
• Acetylated drugs precipitate at acidic or neutral pH in kidney
• Hypersensitivity and hemopoetic disturbances
• Kernicterus (mostly in newborns)
• Bilirubin entering CNS
Contraindications
• Infants under 2 months
• Pregnancy (third trimester)
Trimethoprim
• Inhibitor of bacterial dihydrofolate reductase
• Resembles pteridine moiety of folate
• Decreased conversion of dihydrofolic acid to active folate
• Potency 20 – 50 times more than sulphonamides
• Drug is a weak base
• High concentrations achieved in acidic fluids
• Prostate and vaginal fluids
• Produce effects of folic acid deficiency
• Reverse blood disorders using folinic acid
Co-trimoxazole
• Synergistic antimicrobial activity
• Inhibits two sequential steps in tetrahydrofolic acid
• Trimethoprim is more lipid soluble
• 1:5 ratio trimethoprim:sulphonamide
• Plasma ratio of 1:20
• Adverse effects
• Dermatological and gastrointestinal
• Hematological
• DDI: prolonged prothrombin
4. Inhibitors of protein synthesis
1. Tetracyclines
2. Glycylcyclines
3. Aminoglycosides
4. Macrolides
5. Other:
• Chloramphenicol
• Clindamycin
• quinupristine/dalfopristin
• linezoid
Inhibitors of protein synthesis
• Protein synthesis involves translation of mRNA at the ribosome
• Target bacterial ribosome
• Differ structurally from mammalian cytoplasmic ribosome
• Bacterial ribosome: 70S comprised of 50S and 30S
• Mammalian cytoplasmic ribosome: 80S comprised of 60S and
40S
• Bacterial ribosome resembles mammalian mitochondrial
ribosome
• Mitochondrial toxicity in host
Inhibitors of protein synthesis
Tetracyclines
• Four fused rings with a system of conjugated double bonds
• Oxytetracycline, minocycline, doxycycline, tetracycline
• Broad spectrum, bacteriostatic antibiotics
• MOA
• Enter via passive diffusion and energy-dependent transport
• Concentrate intracellularly
• Bind reversibly to 30S subunit of bacterial ribosomes
• Prevent binding of aminoacyl-tRNA
to mRNA–ribosome complex
• Inhibit bacterial protein synthesis
Tetracyclines
Tetracyclines
• Bind to tissues undergoing calcification
• Cross placenta and concentrate in fetal bones and dentition
• Contraindicated in pregnancy and children
• Widespread resistance limits clinical use
• Mg2+-dependent active efflux mediated by plasmid-encoded
resistance protein
• Enzyme inactivation

Only minocycline
penetrates CNS
Tetracyclines
• Administration with dairy products
or divalent and trivalent cations
(magnesium, aluminum or iron)
decreases absorption
• Formation of non-absorbable chelates
Tetracyclines
Adverse effects
• Gastric discomfort
• Hepatotoxicity
• Deposition in bones and primary dentition
• Discoloration (“orange tooth syndrome”) and hypoplasia
• Vestibular toxicity
• High concentrations (minocycline) in endolymph of ear
• Pseudotumor cerebri
• Intracranial hypertension – headache and blurred vision
• Superinfections
Glycylcyclines* First in class
Approved in 2005

• Tigecycline
• Derivative of minocycline
• Expanded broad spectrum
• Reversibly binds 30S ribosomal subunit
• Prevent amino-acyl tRNA from
binding to the A site of ribosomes
• Inhibits protein synthesis
• Indicated for the complicated skin, tissue infections and complicated intra-
abdominal infections
• Inhibits clearance of warfarin
• Monitor anticoagulation
• Reduce efficacy of oral contraceptives
Aminoglycosides
• Derived from Streptomyces and Micromonospora
• Amikacin, gentamicin, neomycin, streptomycin, tobramycin
• Two amino sugars with glycosidic link to central hexose
• Polycationic, highly polar: difficulty crossing membranes

Streptidine moiety with two

guanido groups linked by a
glycosidic bond
Aminoglycosides
• Diffuse through porin channels in outer membrane
• Oxygen dependent active transports
• Across cytoplasmic membrane via polyamine carrier
• Bind to 30S ribosomal subunit
• Interfere with functional assembly of ribosomes
• And/or cause the 30S subunit of the completed ribosome to misread the
genetic code
Aminoglycosides
Aminoglycosides Associated with
serious toxicity

• Bactericidal
• Empirical therapy against aerobic bacteria
• Not effective against anaerobes: no oxygen transport
• Additive or synergistic effects: β-lactams or vancomycin
• Resistance
• Altered oxygen-dependent transport
• Synthesis of inactivating enzymes:
• Acetyl transferases, nucleotidyltransferases, phosphotransferases
Aminoglycosides
• Dose-related toxicity
• Gentamicin, tobramycin, amikacin
• Ototoxicity (vestibular and cochlear)
• May be irreversible
• Vertigo and loss of balance
• Nephrotoxicity
• Disrupted calcium-mediated processes
• Neuromuscular paralysis
• Inhibition of presynaptic acetylcholine release
• Rare, preventable by slow infusion
• Allergic reactions
Macrolides
• Azithromycin, clarithromycin, erythromycin,
telithromycin
• Irreversibly bind to 50S unit of bacterial
ribosome
• Inhibit translocation steps of protein synthesis
• Bacteriostatic
• Bactericidal at high concentrations
• Alternative in individuals with β-lactam allergy
Telithromycin:
First “ketolide” antimicrobial
Active against many macrolide-resistant strains
Macrolides
• Resistance
• Efflux pumps limit intracellular concentrations
• Decreased affinity for 50S ribosomal subunit
• Plasmid-associated erythromycin esterase
• Reduce destruction of erythromycin by gastric acids
• Enteric-coated tablets or esterified forms
• Azithromycin and clarithromycin differ from
erythromycin
• Broader spectrum of activity
• Longer serum half-live
• Better GI tolerability
Macrolides
• Extensive metabolism
• Inhibit oxidation of other drugs via CYP450 interactions
• Eliminate intestinal flora responsible for warfarin
inactivation
• Adverse effects
• Epigastric distress
• Cholestatic jaundice
• Ototoxicity: transient deafness
• Contraindicated
• Hepatic dysfunction
• Congenital prolongation of the QTc interval
Chloramphenicol
• Broad spectrum: bactericidal or bacteriostatic
• Lipophilic
• Readily enters CSF
• Binds to bacterial 50S subunit
• Inhibits peptidyl transferase reaction
• Inactivated by acetyl coenzyme A transferase
• Disrupts mammalian mitochondrial ribosomes
• Inhibition of host mitochondrial protein synthesis
• Use limited to life-threatening infections for
which no alternatives exist
Chloramphenicol
Adverse effects
• Anaemias (haemolytic, reversible, aplastic)
• Reversible, dose-duration-dependent bone marrow toxicity
• Inhibit hepatic mixed-function oxidases
• Gray baby syndrome (premature babies or neonates)
• Excessive plasma chloramphenicol
• Low capacity for hepatic glucuronylation
• Relatively inadequate renal elimination
• Drug accumulation interferes with mitochondrial function
• Depressed breathing, cyanosis, cardiovascular collapse, death
Clindamycin
• Irreversibly bind to 50S unit of bacterial ribosome
• Inhibit translocation steps of protein synthesis
• Primarily used in treatment of anaerobic
infections
• Well absorbed orally: poor CSF penetration
• Oxidative metabolism to inactive product
• Adverse effects
• Impaired liver function
• Fatal pseudomembrane colitis from C. difficile
overgrowth
• Release necrotizing toxins
Quinupristin/dalfopristin
• Mixture of two streptogramins (30:70)
• Chemically modified derivative from Streptomyces
• Bind to separate sites in 50S bacterial ribosome
• Dalfopristin alters ribosome structure aiding quinpristin binding
• Stable ternary complex synergistically disrupts protein synthesis
• Drug penetrates macrophages and polymorphonucleocytes
• Adverse effects
• Venous irritation, arthralgia, myalgia
• Hyperbilirubinemia
Linezolid
• Combat methicillin and vancomycin resistance
• Spectrum primarily gram (+) organisms
• Inhibits formation of 70S initiation complex
• Bind N-formylmethionyl-tRNA
• Inhibit bacterial protein synthesis
• Bacteriostatic
• Adverse effects
• Thrombocytopenia
• Potential monoamine oxidase inhibition
• Cautioned against excessive tyramine-containing foods

Considered first “new class” of

antibacterial to reach the market
5. Inhibitors of nucleic acid
1. Fluoroquinolones
2. Rifampicin
Fluoroquinolones
• Enter bacterium through passive diffusion via porins
• Interfere with bacterial DNA gyrase and topoisomerase IV
• Responsible for negative supercoil of DNA
• Inhibit resealing, induce DNA cleavage and inhibit replication

• 1st generation: Nalidixic acid (non-fluorinated)

• 2nd generation: Ciprofloxacin, norfloxacin, ofloxacin
• 3rd generation: Levofloxacin
• 4th generation: Moxifloxacin
Fluoroquinolones
• Concentration-dependent bactericidal
• General rule
• Gram-negative bacterial activity
• Inhibition of DNA gyrase
• Gram-positive bacterial activity
• Inhibition of DNA topoisomerase IV

• Clinical uses
• Urinary, respiratory, GI tract infections
• Prostatitis and STIs (gonorrhea)
Fluoroquinolones
• Altered absorption
• Aluminum, magnesium, iron and zinc
• Divalent cations: calcium
• Adverse effects
• CNS: dizziness, insomnia, seizures
• Photosensitivity
• Cardiovascular: QTC prolongation
• Musculoskeletal
• Articular cartilage erosion
• Contraindicated in pregnancy and children under 18
Rifampicin
• Macrolide antibiotic derived from Streptomyces
• Binds β-subunit of bacterial DNA-dependant RNA polymerase
• Inhibits transcription and mRNA synthesis
• Oral bioavailability decreased by food and 1st pass metabolism
• Lipid soluble
Adverse effects
• ’Flu-like’ syndrome, hepatotoxicity
• Drowsiness, mental confusion
• Reddish-orange colouration of body fluids
• Urine, tears, saliva, sweat
Consequences of antibiotic resistance
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Antibacterial resistance
• Classification as resistant if the maximal level of antibacterial
tolerated by the host does not alter bacterial growth
• Genetic alterations
• Spontaneous DNA mutations
• Transfer of DNA
• Protein alterations
• Modification of target site
• Decreased accumulation
• Reduced uptake or increased efflux
• Enzyme inactivation
• Beta-lactamases, acetyltransferases, esterases
Complications of Therapy
• Hypersensitivity or immune reactions
• To antibacterial drugs or their metabolic products
• Direct toxicity
• Directly affecting cellular processes in the host
• Superinfections
• Broad-spectrum antimicrobials or combinations of agents
• Alter normal microbial flora
• Upper respiratory, oral, intestinal, and genitourinary tracts
• Permitting overgrowth of opportunistic organisms
• Require secondary treatments
Antibacterial Abuse
• Irresponsible and erratic use
• 70-80% of prescriptions written unnecessarily
• Lack of confidence in accurate clinical diagnosis
• Shotgun therapy: achieve "dramatic" results
• Peer pressure: 'defensive' practice
• Patient pressure

Non-therapeutic use of antibiotics in animals:

Growth promotion
Metaphylaxis
Lack of Response to Antibacterials
1. Aetiological agent is resistant to specific antibiotic
2. Incorrect diagnosis
3. Correct antibacterial with incorrect dose and/or administration
4. Failure of antibacterial to reach site of infection
5. Secondary infection
6. Non-compliance of the host
7. Foreign body or devitalised tissue that should
be removed
Common situations for abuse
• Premature, presumptive and indiscriminate use adds to cost of
therapy, adverse effects, propagation of drug resistance
• Fever
• Most commonly self-limiting viral infections
• Sore throat
• 10-20% of patients are positive for Streptococci
• 20-40+% of patients receive antibiotics
• Diarrhoea
• Mostly self-limiting and require only adequate rehydration
• Indicated in some circumstances: systemic toxicity, extremes of age, food
poisoning, hemolytic anemia
Rational use of Antibacterials
• Prescribing antibacterials comprises several phases
• Perception of need
• Choice of most appropriate antibiotic
• Choice of regimen: dose, route, frequency and duration
• Monitoring efficacy
• Duration of treatment
• Optimum duration is unknown
• Generally 5-7 days
• Single dose effective in some circumstances
Special considerations: age
• Infants
• Chloramphenicol: grey baby syndrome
• Sulfonamides: kernicterus
• Tetracyclines are contraindicated
• Children below 8 years old
• Tetracyclines are known to discolour teeth
• Children below 18 years old
• Fluoroquinolones are contraindicated
• Arthropathy: damage growing cartilage
Special considerations: age
• Elderly
• Age related physiological changes
• High risk for infectious diseases
• Unique challenge due to multiple co-morbidities, poly-
pharmacotherapy and functional impairments
• Achlorhydria may affect absorption of antibacterial agents
• Reduced drug elimination
• Enhanced ototoxicity of aminoglycosides
Special considerations: pregnancy
• Known toxicity or unestablished safety
• Contraindicated in all trimesters
• Tetracyclines, quinolones
• Streptomycin, erythromycin

• Contraindicated in last trimester

• Sulfonamides, chloramphenicol
Special considerations: pregnancy
• Limited data on safety
• Used of benefit outweighs risk
• Aminoglycosides, azithromycin, clindamycin, vancomycin

• Safe in pregnancy
• Penicillins, cephalosporins, isoniazid

• Contraindicated during lactation

• Sulfonamides, tetracyclines, metronidazole, quinolones
Other approaches
1. Mitotic Inhibitors
2. Ribosome targeting
3. RNA Aptamers
4. Efflux Pumps inhibitors
5. Antibiotic Cycling
Mitotic Inhibitors
• High-resolution structures of PBPs
• Knowledge about the bacterial cell-division pathway
• Target-driven approaches to identify novel inhibitors
• Disrupt microtubules
• Bind tubulin and inhibit its polymerization into microtubules
Ribosome targeting
• Despite size of the ribosome, few sites are targeted
• Antibiotic binding sites on 30S subunit are clustered along
mRNA and tRNAs path
o Improve binding of antibiotic-binding sites of ribosomes
• Target sites on the 50S subunit
• Orthosomycins (evernimycin and avilamycin)
• Thiostrepton-like thiopeptides
• Target sites on the 30S subunit
• Synthetic nitrovinylfuran furvina
• Naturally produced orthoformimycin
RNA Aptamers
• Aptamers are small nucleic acid ligands
• Composed of single-stranded ssDNA or RNA molecules
• High affinity and specificity for pre-selected targets
• Proteins and peptides
• Interesting as therapeutic molecules
• Recognize a specific three-dimensional structure on target
• Termed “chemical antibodies”
• Unique chemical and biological characteristics
Efflux Pumps inhibitors
• Five classes of bacterial multidrug efflux transporters
• Energy for active transport from H+, Na+ or hydrolysis ATP

• Peptidomimetics introduced as efflux pump inhibitors

• Phenylalanine arginyl β-naphthylamide
• Competitive inhibition
• Increased intracellular
antibiotic concentration
Efflux Pumps inhibitors
• Enhance use of traditional antibiotics in combination with EPIs
• Other factors influencing drug efflux
• General membrane properties and organization
• Facilitation of passive ion efflux
• Regulatory genes control multidrug resistance phenotypes
• Co-operation between resistance mechanisms
Antibiotic cycling
• Administer different drugs in strategic succession
• Deliberate removal of antimicrobial of choice in a specific geographic unit
• Reintroduction after a full cycle of alternative antibiotics
• Meta-analyses of clinical data to date have been unconvincing

“This type of traditional drug cycling has at times been shown to

be advantageous, and other times shown to have no effect at all”
• MDR plasmids carry several unrelated resistance determinants

“the practical implication may be that

the bugs are smarter than we are”
Discussion Board Question
A 25-year-old male presents to the urgent care center with a painless sore
on his genitals that started 1 to 2 weeks ago. A blood test confirms the
patient has Treponema pallidum.
a) What is the name of the disease he has been infected with?
b) How is the disease transmitted?
c) What would be the drug of choice for the treatment of this patient’s
infection as a single dose?