3-Nucleic acid synthesis inhibitor antibiotics

Fadhel Ahmed Alomar, Ph.D.

Dept. of Pharmacology, College of Clinical Pharmacy, IAU
• falomar@iau.edu.sa
 3-Nucleic acid synthesis inhibitor antibiotics
 They are bactericidal and interfere with RNA or DNA synthesis
 They are classified into two major antibiotic groups

I. Indirect nucleic acid synthesis inhibitor antibiotics

 They interfere with folate pathway synthesis
o Sulfonamides (e.g Sulfamethoxazole) & Dapsone
o Trimethoprim & pyrimethamine

II. Direct nucleic acid synthesis inhibitor antibiotics (two groups)

1. They inhibit DNA synthesis (Interfere with DNA replication)
o Fluoroquinolones (Ciprofloxacin)
o Nitroimidazoles (Metronidazole)

2. They inhibit RNA synthesis (interfere with RNA transcription )

o Rifampicin
Indirect nucleic acid synthesis inhibitor antibiotics

Interfere with folate pathway synthesis

General concepts for folic acid synthesis inhibitor antibiotics
 Folic acid (a vitamin B9) participates in the nucleic acid synthesis
through transfer one carbon for methylation reactions

 Folate is required for making adenine (A) & guanine (G) & to convert
uracil (U) to thymine (T) as well as to make methionine and glycine ,
THUS
 Folate is essential for DNA & RNA biosynthesis
 Folate is also required for proteins synthesis

 Folic acid synthesis pathway is a target for many antimicrobial

agents that used to eradicate bacterial & parasitic infections
Basis of selective toxicity of folic acid synthesis inhibitor
antibiotics toward bacteria
 The toxic selectivity of these antibiotics come from fact that ...
 Mammalian cells cannot synthesize folate
 Folate is provided in the diet and delivered to mammalian cells
by folate receptors and transporters. THUS,
o Mammalian cells insensitive to drugs that interfere with folic acid
biosynthesis pathway

 Folic acid cannot enter bacterial cells, because bacteria lack the
uptake mechanism transporter of folate. THEREFORE,
o Bacteria must synthesize it de novo from pteridine, para-
aminobenzoic acid (PABA) and glutamate
Basis of selective toxicity of folic acid synthesis inhibitor
antibiotics toward bacteria

Enzyme is not
found in human
(selective toxicity )

Enzyme is Associated with

found in human anticancer S.E.

Methotrexate

DHFR = Dihydrofolate reductase

 Sulfonamides-(sulfamethoxazole)
 They have are a structural analogue of PABA
 Sulfamethoxazole is a bacteriostatic (If used alone)

 Dapsone (Sulfone):
 Is not sulphonamide B/C it does not contains
amide group
 It inhibits dihydropteroate synthase
 It is used in combination with rifampicin to treat leprosy
 Leprosy is an infection caused by the bacterium
Mycobacterium leprae
 Sulfamethoxazole
 Therapeutic uses
 Active against G +ve and G –ve bacteria (Broad spectrum antibiotics )
 Used in combination with trimethoprim to treat a variety microorganism
infections (see trimethoprim)

 Pharmacokinetic
 Is given orally or IV
 Is well absorbed from GIT & widely distributed in the body
 Is mainly metabolized by liver (acetylation)
o Produces a drug with less water soluble than the parent drug
(Problem)-crystaluria
 Sulfamethoxazole
 M.O.A: (Competitive inhibitor of dihydropteroate synthase)

 It competitively inhibits dihydropteroate synthase (DHPS)

 DHPS catalyses the conversion of PABA to dihydropteroate in bacteria
 Ultimately inhibits RNA synthesis and DNA replication

o Procaine may antagonize the antibacterial effect of

sulfamethoxazole (why?)

 Adverse effects:
 Hepatitis, hypersensitivity reaction (SJS )
 Interstitial nephritis or crystalluria results from precipitation of
acetylated metabolite in urine
 Hemolytic anemia (in patients with G6PD deficiency)
 Sulfonamides-(sulfamethoxazole)
 NOW, bacteria resistant to sulfonamides is very common & results from …

I. Increased production of PABA (competitive)

II. Point mutations in dihydropteroate synthase (DHPS) reduce its affinity
for sulfamethoxazole, THUS
 Using these agents as monotherapy is diminished correspondingly

 Sulfamethoxazole is only used in combination with trimethoprim in

a 5:1 ratio (Co-trimoxazole, synergistic , bactericidal & ↓resistance)
o Abbreviated SMX-TMP

 A great degree of synergy occurs between these two drugs as a result

of their inhibition of two different steps in the biosynthesis of THF
 Folic acid inhibitors –Trimethoprim
 Trimethoprim (TMP) is a bacteriostatic drug (if used alone )

 It used in combination with sulfamethoxazole

 Co-trimoxazole is a bactericidal combination that inhibits sequential
steps of folate biosynthesis (synergy and decreased resistance)
 This combination has activities against G +ve and G –ve (E.coli, shigella &
H. influenzae) bacteria as well as protozoa infection

 Therapeutic uses of co-trimoxazole:

 Urinary tract infections (chronic and recurrent infection)

 Travelers' diarrhea & otitis media infection

 Toxoplasmosis (a parasitic disease caused by Toxoplasma gondii)

o Toxoplasmosis can cause lung problem (resemble tuberculosis),
damage brain & inflammation in the eye (particularly among HIV)
 Folic acid inhibitors –Trimethoprim
 Pharmacokinetics
 It is well absorbed from GIT
 Distributed throughout body and it reach high concentration in the
kidney and brain
 It is weak base and eliminated mainly by the kidney
o Lowering urinary pH will enhance the elimination

 M.O.A
 Binds to dihydrofolate reductase (DHFR) & inhibits tetrahydrofolic acid
synthesis ultimately inhibits RNA synthesis & DNA replication

 Selective toxicity comes from bacterial DHFR is thousands-fold more

sensitive to inhibition by trimethoprim than mammalian DHFR
 Folic acid inhibitors –Trimethoprim
 Adverse effects:
 Anticancer like side effects (Bone marrow depression)
particularly in folate-deficient patients

 It is a teratogenic agent and potentially causes fetal

malformations in animal studies (High doses)
o Trimethoprim is classified into category C during pregnancy
by the FDA
 3-Nucleic acid synthesis inhibitors
 They are bactericidal and interfere with RNA or DNA synthesis
 They are classified into two major antibiotic groups

I. Indirect nucleic acid synthesis inhibitor antibiotics

 They interfere with folate pathway synthesis
o Sulfonamides (Sulfamethoxazole) & Dapsone
o Trimethoprim

II. Direct nucleic acid synthesis inhibitor antibiotics (two groups)

1. They inhibit DNA synthesis (Interfere with replication)
o Fluoroquinolones (Ciprofloxacin)
o Nitroimidazoles (Metronidazole)

2. They inhibit RNA synthesis (interfere with transcription )

o Rifampicin
Direct nucleic acid synthesis inhibitor antibiotics
 1-Fluoroquinolones
 Prototype – Ciprofloxacin (Cipro®)
 Levofloxacin, ofloxacin and moxifloxacin
 They are bactericidal and interfere with DNA synthesis
 They have broad spectrum activities against G +ve /G –ve bacteria including
many organisms resistant to penicillins, cephalosporins & aminoglycosides

 Therapeutic uses
 Used orally & parenterally (IV) to treat urogenital, complicated UTI (e.g
pyelonephritis) and respiratory infections

 They are used to treat STD such as chlamydia & gonorrhea

 Used as prophylaxis for anthrax in individual who have inhaled spores

 Moxifloxacin has an excellent activity against many of anaerobes

bacteria and has very poor activity against P aeruginosa
 1-Fluoroquinolones
 Pharmacokinetics

 They are well absorbed after oral administration

 They are distributed throughout body & accumulated in several organs

such as lung, kidney and prostate

 They also concentrated in phagocytes ( used as 2nd line for T.B)

 All fluoroquinolones can cross BBB EXCEPT ofloxacin

o Ofloxacin cannot cross BBB

 Ca2+, Al3+ & Mg2+ interfere with absorption of fluoroquinolones, THUS

o Like TCs , they should not be administered with milk & antacid
preparations
 1-Fluoroquinolones (e.g Ciprofloxacin)
 M.O.A (bactericidal antibiotics )

 They are a bactericidal antibiotics

 They inhibit topoisomerase II

 Topoisomerase II (DNA gyrase) removes positive supercoiling that

accumulated during the DNA replication via introducing negative

supercoils into DNA, so that replication can continue

 Fluoroquinolone antibiotics bind to & inhibit DNA gyrase enzyme

accumulation of positive supercoiling inhibition of DNA transcription

ultimately result in the death of microorganisms

 1-Fluoroquinolones (Ciprofloxacillin)
 Mechanism of fluoroquinolones resistance
 Resistance results from mutation in the bacterial DNA gyrase as well as
reduced the bacterial membrane permeability to fluoroquinolones

 Adverse effects:
 Tendon rupture
o Not recommended for children bellow 18 years
 Prolong the heart's QT interval (Cardiac arrhythmia )
 Visual disturbance

 Drug-drug interaction

 Inhibit P450 enzyme → increase plasma levels of warfarin & theophylline

 2-Nitroimidazoles-Metronidazole
 Therapeutic uses
 It is a bactericidal antibiotic that has activities against a wide variety of
anaerobic bacteria and protozoal parasites
 It is DOC for treatment of clostridium difficile-associated diarrhea
 It is DOC for treatment amoebiasis
 It is DOC for treatment giardiasis (a sexually transmitted disease)
o All sexual partners should be treated

 M.O.A
 It is a prodrug that reduced to its active form inside organisms
o Reduction of metronidazole happens only in anaerobic cells and
parasites (not on human cells or aerobic bacteria (selective toxicity)
 The reduced metronidazole covalently binds to DNA, disrupts its helical
structure & inhibits the nucleic acid synthesis → microorganism death
 Nitroimidazoles-Metronidazole
 Adverse effects:
 Metallic taste in the mouth & dark urine

 Drug interactions
 Disulfiram-like reaction with ethanol (An alcohol hangover symptoms)

Toxic & Carcinogenic Harmless

 Disulfiram blocks ALDH causing build up of acetaldehyde → unpleasant

symptoms (hangover); nausea, drowsiness, headache, tachycardia,
shortness of breath & hyper-excitability that may last more than 24 hours
Thank you very much
Model depicting the possible routes of folic acid uptake into neuroepithelial cells. Soluble
FOLR1 (sFOLR1) and GPI-anchored FOLR1 bind to folic acid, and the uptake of the
complex is mediated through endocytic mechanisms. High-efficiency internalization of
sFOLR1 and GPI– FOLR1 relies on their interaction with a co-receptor spanning the plasma
membrane, which, according to our results, is likely to be LRP2 (route 1 and 2). Less-
efficient uptake is probably mediated by alternative routes (3), which are not yet well