8. Abx Targeting Nucleic Acids Pt 2
This is paul ekberg from the division of infectious diseases at stanford university this video is intended to be part 2 in the discussion of antibiotics that target nucleic acids sometimes loosely referred to as dna synthesis inhibitors or dna damages the fluoroquinolones were discussed in part one while other classes that target nucleic acids will be discussed
Here in part two including the rhythm ison’s the folate synthesis inhibitors and the nitro imidazoles learning objectives include describe the differences in mechanism of action between the lapierre my license and the rhythm ison’s state the sole clinical indication for fidaxomicin list the main adverse effects associated with the rhythm ison’s describe how
Trimethoprim and sulfamethoxazole are synergistic in combination and described a unique mechanism of action of metronidazole and how it limits a spectrum of activity and clinical use as mentioned the fluoroquinolones were discussed in part one of antibiotics that target nucleic acids in this part 2 video we will focus on the rna polymerase inhibitors the folate
Synthesis inhibitors and the dna damages all highlighted in yellow in the upper right corner first we will cover the rna polymerase inhibitors consisting of two main classes of antibiotics the lip eerm ison’s and the rhythm ison’s the figure on the left depicts the site of action of these two classes at a very basic level the lip your my son’s in the top part of the
Figure block transcription by binding to rna polymerase and dna prior to formation of the open dna complex however specific details of this mechanism remain unknown recall that transcription is the first step of gene expression where dna is copied into messenger rna in contrast the rhythm ison’s block a later stage of transcription by binding to the beta subunit
Of rna polymerase the inhibition of transcription by either class is bactericidal in nature the lippy erm ison’s our new kids on the block as you can see in the blue box there is only one representative member of this class available in the u.s. called fidaxomicin which was fda approved in 2011 the structure shows similarity with the macrolide class of antibiotics
But fidaxomicin is bactericidal rather than bacteriostatic and has a very narrow spectrum of activity namely clostridium difficile therefore it’s only indication is the treatment of clostridium difficile associated disease it’s poor activity versus other anaerobes prevents a wider destructive effect on the intestinal microbiota not a lot is known about resistance
Development in vivo in part because of its novelty and relatively rare use fedex m ison is very well tolerated which might be related to the fact that this agent is not systemic ly absorbed to any extent that is drug concentrations remain secluded to the intestinal tract lumen after oral administration this property is similar to that of oral vancomycin which you
Heard about in the cell wall inhibitors video rhythm ison’s are potent rna polymerase inhibitors that have a broad spectrum of activity as shown here in the first bullet however it’s important to note that this class of agents is primarily used in the treatment of mycobacterial disease namely tuberculosis and therefore these agents will be covered in more detail
And mycobacterial and tuberculosis videos one exception is the newest trifa meissen called rif aksum in which is similar in some ways to fidaxomicin discussed on the prior slide in that this agent is not systemic li absorbed from the intestines and achieves high intraluminal concentrations it is used primarily as a second-line agent for gastroenteritis especially
Travelers diarrhea adverse effects include orange discoloration of the urine sweat or tears you can see this in the lower right hand picture thrombocytopenia which has decreased platelets hepatic effects such as non-obstructive cholestasis with an increased level of bilirubin in the blood and rarely drug-induced hepatitis and renal dysfunction which is rare
Finally this class of agents can induce the metabolism of other drugs metabolized by the cytochrome p450 system leading to important drug drug interactions in decreasing the serum levels of other drugs to potentially non therapeutic levels we will now shift gears to the folic acid synthesis inhibitors which constitute two antibiotic classes that inhibit foley
Synthesis at different points along the folic acid synthesis pathway as shown here in the figure the first is the sulfonamide class and the second is the benzyl perimeter class their enzymatic targets are highlighted by the red symbols in the figure namely dihydrate arrow 8 synthetase and dihydrofolate reductase respectively focusing on the sulfonamides first in
The blue box note that the dihydrate arrow 8 synthetase target is unique to bacterial cells most bacteria can’t take up exogenously from the environment and they must synthesize it from para amino benzoic acid or pa ba also seen in the figure above though sulfonamides are structural analogs of pa ba and they compete with pa ba and bind to and inhibit dihydrate
Arrow a synthetase this blocks folic acid production which is essential for purine and dna synthesis the benzyl perimeters in the lower right-hand corner are structurally similar to dihydrofolate acid these compounds bind to and inhibit dihydrofolate reductase which is not unique to microorganisms however the drugs in this class are much less potent versus the
Human form of this enzyme then the bacterial forms note that trimethoprim is antibacterial and it’s almost always administered in combination with sulfamethoxazole as a fixed combination called tmp smx as you can see here in the yellow circle this is trimethoprim sulfamethoxazole in contrast pure meth amine another benzyl permitting is anti-parasitic and will be
Discussed in a separate video on protozoa affections although resistance mechanisms won’t be described in any detail here you can surmise how bacteria might develop resistance to these agents sulfonamide resistance might result from overproduction of pa ba or via dye hydro tarot 8 synthetase mutations which would have low affinity for sulfonamides similarly
Trimethoprim resistance might result from overproduction of dihydrofolate reductase or via dihydrofolate reductase mutations with low affinity for trimethoprim as mentioned trimethoprim sulfamethoxazole is a synergistic combination of two folate synthesis inhibitors on this slide i will briefly mention the spectrum of activity and the common clinical uses
Of this combination with regard to clinical uses this drug used to be one of the mainstays of therapy for urinary tract infection and still is in areas with low prevalence of gram-negative rodri systems however its widespread use has been impacted by a dramatic rise in resistance over recent years especially among ecoli isolates you might recognize that this
Scenario is very similar to that described for fluoroquinolone use in this infection as reviewed in the quinolones video trimethoprim sulfamethoxazole is also used in a few uncommon infectious diseases such as whipple’s disease shigellosis and infections caused by stenotrophomonas multi philia which is a bacterium that causes nose a kamiel pneumonia and other
Noza kamiel infections i encourage you to read about these uncommon infections on your own trimethoprim sulfamethoxazole is associated with a few key adverse effects hypersensitivity is the most common the accompanying picture demonstrates this very severe rash called erythema multiforme ii also called stevens-johnson syndrome which is associated with sulfonamide
Use hypersensitivity can also be manifested by nonspecific rashes hepatitis nephritis or even drug fever gastrointestinal effects are common including nausea vomiting and diarrhea as you’ve heard me say a number of times with numerous antibiotic classes precipitation in the urine can lead to crystal area and associated abnormalities detected on urinalysis however
This does not commonly alter renal function itself hematological abnormalities can affect any blood cell line whether low white cells low red blood cells or low platelets and finally this drug is contraindicated in pregnancy as drug-related hyperbilirubinemia or elevated bilirubin levels in the blood and the pregnant mother can lead to accumulation of bilirubin in
The basal ganglia or other deep gray matter of the brain in the growing infant called kernicterus which has neurotoxic and has the potential to lead to severe brain damage in the child finally we will briefly discuss the nitro middle-class of which there is one available member in the united states called metronidazole similar to trimethoprim sulfamethoxazole this
Agent has both protozoa and bacterial activity that we will focus here on it’s antibacterial activity which is restricted to the anaerobic bacteria this unique spectrum of activity can be explained by its mechanism of action metronidazole is selectively absorbed by anaerobes and partially reduced inside the anaerobic bacterial cell to toxic metabolites depicted
In the accompanying figure these metabolites directly damage dna leading to cell death regarding clinical uses metronidazole is most commonly used in combination with other agents for to aerobic anaerobic infections such as intra-abdominal infections or polymicrobial bringing abscesses metronidazole is also used as mono therapy for certain types of vaginitis
Trichomoniasis and bacterial vaginosis and also for c difficile associated disease note that metronidazole remains as one of the front-line therapies for this particular infection finally key adverse effects are listed in the last bullet including gi and tolerance such as nausea and vomiting some patients might experience a metallic taste others may experience a
Disulfiram like reaction therefore concomitant alcohol use should be prohibited and finally among patients who might receive very high doses or very long durations of this drug might experience a very rare peripheral neuropathy
Transcribed from video
Intro to Bacteria & Antibiotics: Abx Targeting Nucleic Acids Pt 2 By RWJF Microbiology Immunology \u0026 Infectious Diseases
