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Trimethoprim is a synthetic antimicrobial compound that serves as an antimetabolite within the same folic acid synthesis pathway as sulfonamides. However, trimethoprim is a structural analogue of dihydrofolic acid and inhibits a later step in the metabolic pathway ( [link] ). Trimethoprim is used in combination with the sulfa drug sulfamethoxazole to treat urinary tract infection s, ear infection s, and bronchitis . As discussed, the combination of trimethoprim and sulfamethoxazole is an example of antibacterial synergy. When used alone, each antimetabolite only decreases production of folic acid to a level where bacteriostatic inhibition of growth occurs. However, when used in combination, inhibition of both steps in the metabolic pathway decreases folic acid synthesis to a level that is lethal to the bacterial cell. Because of the importance of folic acid during fetal development, sulfa drugs and trimethoprim use should be carefully considered during early pregnancy.

The drug isoniazid is an antimetabolite with specific toxicity for mycobacteria and has long been used in combination with rifampin or streptomycin in the treatment of tuberculosis . It is administered as a prodrug, requiring activation through the action of an intracellular bacterial peroxidase enzyme, forming isoniazid-nicotinamide adenine dinucleotide (NAD) and isoniazid-nicotinamide adenine dinucleotide phosphate (NADP), ultimately preventing the synthesis of mycolic acid, which is essential for mycobacterial cell walls. Possible side effects of isoniazid use include hepatotoxicity , neurotoxicity , and hematologic toxicity ( anemia ).

PABA binds to an enzyme to produce dihydrofolic acid, which binds to another enzyme to produce tetrahydrofolic acid and nucletides. Trimethoprim, a structural analog of dihydrofolic acid, completely inhibits the synthesis of tetrtahydrofolic acid. Sulfonamide, a structural analog of PABA, competitively inhibits the synthesis of dihydrofolic acid.
Sulfonamides and trimethoprim are examples of antimetabolites that interfere in the bacterial synthesis of folic acid by blocking purine and pyrimidine biosynthesis, thus inhibiting bacterial growth.
Antimetabolite Drugs
Metabolic Pathway Target Mechanism of Action Drug Class Specific Drugs Spectrum of Activity
Folic acid synthesis Inhibits the enzyme involved in production of dihydrofolic acid Sulfonamides Sulfamethoxazole Broad spectrum against gram-positive and gram-negative bacteria
Sulfones Dapsone
Inhibits the enzyme involved in the production of tetrahydrofolic acid Not applicable Trimethoprim Broad spectrum against gram-positive and gram-negative bacteria
Mycolic acid synthesis Interferes with the synthesis of mycolic acid Not applicable Isoniazid Narrow spectrum against Mycobacterium spp., including M. tuberculosis
  • How do sulfonamides and trimethoprim selectively target bacteria?

Inhibitor of atp synthase

Bedaquiline, representing the synthetic antibacterial class of compounds called the diarylquinolones , uses a novel mode of action that specifically inhibits mycobacterial growth. Although the specific mechanism has yet to be elucidated, this compound appears to interfere with the function of ATP synthases, perhaps by interfering with the use of the hydrogen ion gradient for ATP synthesis by oxidative phosphorylation , leading to reduced ATP production. Due to its side effects , including hepatotoxicity and potentially lethal heart arrhythmia, its use is reserved for serious, otherwise untreatable cases of tuberculosis .

Part 2

Reading thorough Marisa’s health history, the doctor noticed that during her hospitalization in Vietnam, she was catheterized and received the antimicrobial drugs ceftazidime and metronidazole . Upon learning this, the doctor ordered a CT scan of Marisa’s abdomen to rule out appendicitis; the doctor also requested blood work to see if she had an elevated white blood cell count, and ordered a urine analysis test and urine culture to look for the presence of white blood cells, red blood cells, and bacteria.

Marisa’s urine sample came back positive for the presence of bacteria, indicating a urinary tract infection (UTI). The doctor prescribed ciprofloxacin. In the meantime, her urine was cultured to grow the bacterium for further testing.

  • What types of antimicrobials are typically prescribed for UTIs?
  • Based upon the antimicrobial drugs she was given in Vietnam, which of the antimicrobials for treatment of a UTI would you predict to be ineffective?

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Key concepts and summary

  • Antibacterial compounds exhibit selective toxicity , largely due to differences between prokaryotic and eukaryotic cell structure.
  • Cell wall synthesis inhibitors, including the β-lactams , the glycopeptides , and bacitracin , interfere with peptidoglycan synthesis, making bacterial cells more prone to osmotic lysis.
  • There are a variety of broad-spectrum, bacterial protein synthesis inhibitors that selectively target the prokaryotic 70S ribosome, including those that bind to the 30S subunit ( aminoglycosides and tetracyclines ) and others that bind to the 50S subunit ( macrolides , lincosamides , chloramphenicol , and oxazolidinones ).
  • Polymyxins are lipophilic polypeptide antibiotics that target the lipopolysaccharide component of gram-negative bacteria and ultimately disrupt the integrity of the outer and inner membranes of these bacteria.
  • The nucleic acid synthesis inhibitors rifamycins and fluoroquinolones target bacterial RNA transcription and DNA replication, respectively.
  • Some antibacterial drugs are antimetabolites , acting as competitive inhibitors for bacterial metabolic enzymes. Sulfonamides and trimethoprim are antimetabolites that interfere with bacterial folic acid synthesis. Isoniazid is an antimetabolite that interferes with mycolic acid synthesis in mycobacteria.

Fill in the blank

Selective toxicity antimicrobials are easier to develop against bacteria because they are ________ cells, whereas human cells are eukaryotic.

prokaryotic

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True/false

β-lactamases can degrade vancomycin.

false

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Short answer

If human cells and bacterial cells perform transcription, how are the rifamycins specific for bacterial infections?

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What bacterial structural target would make an antibacterial drug selective for gram-negative bacteria? Provide one example of an antimicrobial compound that targets this structure.

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Questions & Answers

full life cycle of plasmodium parasite
Emmah Reply
what are ways of handling sharps
namugenyi Reply
never recap or bend a sharp objects
benita
describe the process of platelet formation
Joy Reply
what is parasitic helminths
Sadiya Reply
list three categories of symbiotic relationships.
mary Reply
what's the difference between microbial intoxication and infectious diseases
dranimva Reply
microbial intoxication results when a person ingests a toxin or a poisonous substance that has been produced by a microbe while infectious disease results when a pathogen colonize the body and subsequently cause disease.
mary
weighing balance is needed in lab of microbiology for weighing?
amna Reply
It is mainly used for media preparation and product testing purpose.
Nakaweesi
thank you for your joining
nuur
what is microbiology
Shamsuddeen Reply
study of living organisms that are too small to be visible with naked eye
Marah
yes
Ahmed
microbiology is the study of microscopic organisms, either unicellular(single cell), multicellular( cell colony), or acellular (lacking cell).
munachimso
is the word Atypical or a typical bacteria. .am confused pliz help
MUWANGUZI Reply
typical bacteria
Zulpha
okay thank you what does that mean
MUWANGUZI
atypical means that it has some characters from bacteria not all characters ...but tybical means that it has all the characters that bacteria have
Reham
thank you Zulpha
MUWANGUZI
some examples please
MUWANGUZI
thank you Reham
MUWANGUZI
1) typical bacteria contain a cell wall whereas atypical bacteria usually do not contain a cell . 2) typical bacteria can be either Gram-positive or Gram-negative while atypical bacteria remain colorless with Gram staining. 3) cells of typical bacteria are large ,while cells of the atypical small
Marah
Example of atypical : Mycoplasma pneumoniae , chlamydophila pneumoniae , legionella
Marah
what is micro biology
Jauharah Reply
is the study of organisms which can't be viewed by our necked eyes
Egumat
Because it preexisting causing secondary infection after collateral damage of normal microbota
Rafaa Reply
combinations of drugs that can't be taken together and why
Grace Reply
Antagonism: the combined action is less than that of the more effective agent when used alone). All these effects may be observed in vitro (particularly in terms of bactericidal rate) and in vivo والله اعلم
Lenovo
....fermentros have 1-15litre capacity
AMAR Reply
which of the following microorganisms are classified as eukaryotic?
Semugab Reply
how do I see the list?
Melissa
what are the choices?
Melissa
dear tell us the choices
MUWANGUZI
mr semugab give us the list please
Nambi
Fungi
munachimso
what are the new discoveries of microorganisms
Ezibon Reply
bacteriology,viriology,micrology
Egumat

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Source:  OpenStax, Microbiology. OpenStax CNX. Nov 01, 2016 Download for free at http://cnx.org/content/col12087/1.4
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