Antimicrobials Flashcards
-cidal Antimicrobials
- Faster onset
- Functional immune syst not required
- Used in immunocompromised individuals
- Used in life-threatening infections
-static Antimicrobials
- Slower onset
- Does require functional immune system in pt
- Not advised in immunocompromised individuals
- Not advised in life-threatening infections
Selective Toxicity
Goal: minimal/no effect against host but maximum effect against infecting microorganism
*low selective toxicity = higher risk of side effects
Broad-spectrum Antimicrobials
Effective against a wide range of infectious micro organisms which includes both G+ve and G-ve bacteria
Narrow-spectrum Antimicrobials
Active against selected group of bacterial types
Broad-spectrum Used when:
Wide differential dx, delayed tx to identify microorganism would be detrimental to pt, tx of drug resistant pathogens where their resistance is to narrow spectrum compounds, or polymicrobial infections
Synergistic Interaction
Compounds are more effective in combination with one another
E.g. - penicillin is -static on its own but add genamicin the duo becomes -cidal
Target sites for Abx:
- Metabolism
- Protein synthesis
- CW
- Nucleic acid synthesis
Sulfonamides
Target: folic acid synthesis
Structure: analog of PABA (component of folic acid in bacteria)
Selective toxicity: no equivalent mammalian pathway (bacteria must synthesize their own folic acid)
Cyclines
Mechanism: bind aminoacyl site of 30s ribosome; aminoacyl tRNA is unable to bind bc of this
Aminoglycosides
Mechanism: interfere w/ formation of 30S initiation complex
Macrolides
Mechanism: bind to 23S component of 50S rRNA, blocks exit of peptide chain
Inhibitors of PG/CW synthesis
Groups: penicillins, cephalosporins, monobactgams, carbapenems
*bacteria must be actively replicating for these compounds to work (active ONLY on growing cells)
B-lactams
Target: mecA gene that encodes for penicillin binding protein (PBP) aka transpeptidases
Mechanism: interfere w/ transpeptidase enzymes that cross-link the PG/CW of the bacterium, the (must be replicating/growing) microorganism will lyse
Effect: bacterial cell lysis
Inhibitors of nucleic acid synthesis
Mechanism: inhibitors of DNA gyrase
Quinolone: synthetic abx
Fluoroquinolone: addition of side chain to quinolone to change the activity of the abx
Inherent Resistance
- Lack of target for drug to act against (mycoplasma has no CW so resistant to penicillin)
- Structural restriction (G-ve outer membrane blocks abx access)
Acquired Resistance
Via genetic diversity the bacterium transfer resistant genes to offspring, and random mutations occur causing resistance
Aminoglycosides
Ineffective against: anaerobes
Reason: ox-phos is absent in anaerobes
Glycopeptides
Ineffective against: G-ve
Reason: large abx and can’t penetrate the outer membrane
Nitroimidazoles
Ineffective against: aerobes
Reason: aerobes lack flavodoxin (which activates the nitroimidazoles)
Altered Uptake
Decrease/block uptake to prevent intracellular accumulation of abx to therapeutic level
Mechanism: often involves multi-drug resistance efflux pumps
Altered Target
Change in receptor site affinity, reduces binding of abx to cellular target
Mechanism: mecA gene encodes for a modified transpeptidase (so there is lower binding affinity for B-lactam abx)
*no inhibition of CW synthesis
Drug Inactivation
B-lactamases, chloramphenicol acetyltransferases
Mechanism: hydrolytic enzymes that cleave the abx, constitutive or inducible
*partial solution: give Abx plus B-lactamase inhibitor
Extended-Spectrum B-Lactamases
Allow bacteria to be resistant to almost all B-lactam abx, and frequently to aminoglycosides and fluoroquinolones
Exceptions: Cephamycins and Carbapenems
*main producers are E. coli and Klebsiella
Transformation (recombination)
Uptake of DNA released by bacterial cell lysis, facilitated by DNA binding proteins, requires Ca2+, bacterial cell is called “competent cell” if it does transformation
Conjugation (recombination)
Acquisition of free-floating DNA by plasmid called F factor which codes for a sex pilus, the cell w/ plasmid called F+ comes in contact with the F- cell an F- becomes F+
**only in G-ve bacteria
Transduction (recombination)
Mediated by bacteriophages (bacterial viruses), in temperate virus the phage DNA integrates w/ host cell DNA
*e.g. - Diptheria toxin
Transposition (recombination)
Transposon mediated non-homologous recombination, transposons are mobile genetic elements and can move around w/in the cell
*aka “jumping genes”
Flucytosine (5-FC)
What? pyrimidine analogue
Mechanism: intracellular deamination of drug to 5-FC by fungal cytosine deaminase
Effect: inhibits synth of DNA, RNA and proteins
*fungicidal activity against Candida and Cryptococcus
Polyenes
Mechanism: binds to Ergosterol in fungal cell membrane, causes pores in the membrane disrupting osmotic integrity then ion leakage and membrane destabilization
Effect: cell lysis due to disruption of membrane stability
*fungicidal activity against most yeasts and filamentous fungi
Azoles
Target: Ergosterol (250-fold affinity for fungal sterols)
Mechanism: stops ergosterol synthesis by binding to 1,4a-demythylase
Effect: hinder growth can be fungistatic or fungicidal depending
*some have anti-parasitic effects
Fluconazole
Azole drug that targets Lanosterol
Echinocandins
Target: (1,3)-B-D-glucan synthase
Mechanism: disrupts CW (chitin) formation
Resistance: dec affinity for (1,3)-B-D-glucan synthase
Neuraminidase Inhibitors
Target: neuraminidase (influenza virus) which normally cleaves sialic acid from glycoproteins to prevent virus being trapped in mucus
Mechanism: blocks neuraminidase causing formation of viral aggregates at cell surface (i.e. release is blocked)
E.g. - Oseltamivir
IFNs (viral interference)
Mechanism: stimulate uninfected cells to produce antiviral proteins
Affect: blocks transcription and protein synthesis
Acyclovir
Compound: nucleoside analog (guanine)
Mechanism: viral thymidine kinase is only present in virally infected cells and is required to activate Acyclovir, it is the first enzyme needed to convert ACV from monophosphate to diphosphate (most important step)
Effect: chain termination (HSV 1 and 2)
Viral load
Amount of virus present in plasma, CSF, or other fluids
- copies of nucleic acid per ML
- monitors antiretroviral therapy in HIV
Integrate Strand Transfer Inhibitors (INSTIs)
Target: integrase enzyme
Mechanism: blocks bonding of host and viral DNA so it can’t be incorporated into genome
E.g. - Raltegravir and Elvitegravir
Reverse Transcriptase Inhibitors (RTIs)
Target: Reverse Transcriptase Mechanism: prevents viral RNA to DNA Types of RTIs: 1. NucleoSide analogues (NRTIs) 2. NucleoTide analogues (NtRIs) 3. Non-nucleoside (NNRTIs)
Nitroimidazole
Characteristics: antiparasitic and antibacterial (against anaerobes)
Mechanism: ferredoxins donate electrons to nitro group of drug and activate to reduced form; acts as terminal electron acceptor and binds to DNA
Effect: loss of helical structure of DNA, impaired ability to act as template, breakage of strand
Pentamidine
Antifungal, antiprotozoal (giardiasis and cryptosporidosis)
Mechanism: inhibition of DNA, RNA and protein synth
*toxic; largely replaced by other compounds now
Antimalarials
- single drug usually targets single stage of the Plasmodium lifecycle (blood or liver, etc)
- stage specificity can vary w/ Plasmodium species
E.g. - quinines, doxycycline (protein synth inhib), artemisinin
Aminoquinoline Analogs
Likely mechanism: interferes w/ parasites he matin detoxification
*blood schizontocides
Doxycycline
Mechanism: interferes w/ apicoplast (disrupts 70S ribosome)
Effect: inhibits protein synthesis
Target: both blood and liver stages of plasmodium
Artemisinin
Mechanism: release free-radicals into parasite vacuoles, damaging membranes
Effect: inhibition of major metabolic processes like glycosiysis
*usually combined w/ aminoquinolone (ACT) to delay dev of resistance
Ivermectin
Mechanism: interfere w/ Glu-gated Cl channels resulting in hyperpol of cells
Effect: paralysis and death of parasite
Target: nematodes, crestodes, and trematodes
*potent against: onchocerciasis and lymphatic filariasis
Benzimidazoles
Mechanism: binds to beta-tubulin of cytoskeleton and inhibits something we dk what?
Target: intestinal nematodes, various cestodes
E.g. - Albendazole and Mebendazole
Praziquantel
Mechanism: interferes w/ Ca2+ transport in tegument
Effect: worm paralysis (detachment, breakdown and expulsion)
Target: trematodes and crestodes (e.g. - liver flukes, cysticercosis, schistosomiasis)
Biofilms (inherent resistance)
Multiple Abx cannot target the species that produce biofilms due to reduced microbial metabolic activity; lack of penetration
NucleoSide and NucleoTide Analogues
Both lack 3’ hydroxyl group which causes chain termination because the polymerase cannot add on to the N3 group
Amantadine/Rimantadine
Target: inhibit uncoating
Mechanism: viral M2 protein blocked so viral RNAs remain bound to M1, H+ ion channel formation is disrupted and viral RNA can’t enter nucleus
Affect: viral replication halted
Antiparasitic Resistance (malaria)
Mutation, change in gene copy # causing change in drug target or increased efflux pumps
Oseltamivir (Tamiflu)
Target: NA
Mechanism: virus binds to its own sialic acid and forms useless clumps blocking release/budding from host cell
