Biology 260Biology 260 Model Building Exercise 02 (Version 05)Stage 02 – Antimicrobials:...

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Biology 260Biology 260    Model Building Exercise 02 (Version 05)Stage 02 – Antimicrobials: Susceptibility & Resistance Building a model to explain a natural phenomenonNatural Phenomenon: Antimicrobial drug resistance is an enormous global health problem.  Many bacteria and viruses were once susceptible to many different antimicrobials, but now they are becoming resistant.  How does antimicrobial drug resistance happen??BACTERIA: ANTIMICROBIAL SUSCEPTIBILITYOur back story: Now that a pathogenic bacterium has been transmitted to our patient by getting past our microbial control methods, has made it past the patient’s normal microbiota, has found the right environment and nutrients, has harvested energy, and has grown through binary fission, and we’ve gone from one bacterium to a population of millions of bacteria causing tissue damage and disease, our patient is given an antimicrobial.  1. Explain what a biofilm is (p.94), how it forms, and how it can protect a population of bacteria from the environment (which includes antimicrobial drugs, microbial control methods, and the immune system).2. What does it mean for a population of bacteria to be susceptible to a drug?    Table 1.  List of antibacterial drug classes    i. Beta-lactam drugs (penicillins, cephalosporins, caapenems, monobactams)     ii. Glycopeptide drugs    iii. Bacitracin    iv. Protein synthesis inhibitors (aminoglycosides, tetracyclines, glycylcyclines, macrolides, chloramphenicol, lincosamides, oxazolidonones, pleuromutilins, streptogramins)    v. Fluoroquinolones    vi. Rifamycins    vii. Metronidazole    viii. Trimethoprims + Sulfonamidesa. For each class of antimicrobial above, describe i. the cell synthesis process that it inhibits (cell wall synthesis, protein synthesis, nucleic acid synthesis, biosynthesis) ii. the target of the class of drugs (what protein or molecule does it bind to?), iii. where in the cell you would find that target, iv. how this class of antimicrobials kill or inhibit bacteria, andv. how this class of antimicrobials exhibits selective toxicity.. Many of these antimicrobials work through competitive or noncompetitive inhibition of the specific enzyme or molecule (a target) that is required for these synthesis pathways.  Describe how competitive and non-competitive inhibition work (review from Bio160).c. Draw or copy and paste a Gram-positive and a Gram-negative cell wall and cytoplasmic memane (See Figure 3.32 and XXXXXXXXXXMake sure to include all of the structures and label each structure.i. On those pictures: 1. Name, draw, and label the targets of the antimicrobials in Table 2 below 2. Draw and explain how these drugs (Table 2) gain access to their targets.    Table 2.  List of antimicrobials    ertapenem    azithromycin    co-trimoxazoleANIMAL VIRUSES: ANTIMICROBIAL SUSCEPTIBILITYHow do animal viruses replicate?  How can we use this information to explain how antiviral drugs work?  In your answer explain how the following two viruses replicate:    Table 3.  List of viruses    Special structures to label    Synthesis and Assembly Enzymes    Antiviral drugs    HIV    gp120, gp41    Reverse TranscriptaseIntegraseProtease    1. Entry (attachment) inhibitors (provide specific example of a drug)2. Nucleic acid synthesis inhibitors (provide specific example of a drug)3. Assembly inhibitors (provide specific example of a drug)    Influenza    Hemagglutinin and Neuraminidase* Explain what H3N2 and H1N1 means    RNA-dependent RNA Polymerase    1. Viral uncoating inhibitors (Influenza) (provide specific example of a drug)2. Release inhibitors (Influenza) (provide specific example of a drug)For each virus explain the following:1. Draw the structures of the virus (refer to Table 3 for special structures to label).i. Label the nucleic acid (is it RNA or DNA?), capsid, envelope, spikes2. Explain if the virus infection results in eithea. a productive infection and/o. a latent state?3. Explain how the virus replicates? (see your textbook and reliable outside sources for information; cite your outside sources)a. Attachment i. What are the host cell receptors (name them)? What viral spikes bind to these receptors (name them)?. Penetration and uncoating  i. Explain whether the virus uses memane fusion entry or endocytic entry. c. Synthesis of viral genome and Assembly of new viruses i. Using the enzymes listed in Table 3, explain how the virus replicates its viral genome and assembles new viruses.d. Releasei. For Influenza – Explain how neuraminidase works.4. Explain how each type of antiviral drug in Table 3 works: (See your textbook for information on these).a. What viral enzyme or molecule does it bind to?. What replication process does it inhibit? (Attachment? Uncoating? Synthesis of viral genome? Assembly of virus? Release of virus?)c. Provide a specific name of a drug as an example.  See your textbook.HOW DOES ANTIMICROBIAL DRUG RESISTANCE HAPPEN?BACTERIA: ANTIMICROBIAL RESISTANCE2. However, over time, that population of bacteria, once susceptible to the antimicrobial, is now resistant.a. How can a bacterium resist an antimicrobial drug?  Resistance traits!!  Explain how each of these causes antimicrobial resistance:i. Drug-inactivating enzymesii. Increased eliminationiii. Decreased uptakeiv. Alteration in target molecule. How can a population of bacteria become resistant?   Natural Selection!  Make sure to include in your explanation the following underlined key words:i. Resistance traits are random pre-existing variations in a population1. Random base substitution mutations during DNA replicationa. Explain the difference between silent, missense, nonsense, and frameshift mutations.  . What might be the effect on the protein structure and function as a result of each type of mutation?2. Horizontal gene transfer (how does this differ from vertical gene transfer?)a. Transformation (key words)i. Donor DNA, competent (recipient) cell, single-strand of DNA, homologous recombination. Transduction (key words)i. Bacteriophage, host (donor) cell, cut host DNA into pieces, transducing particle, recipient cell, homologous recombination.c. Conjugation i. Explain how conjugation happens between an F+ donor cell and an F- recipient cell.ii. Explain what an R plasmid is and describe the type of genes you could find on it (pilus-synthesis genes, drug-resistance genes)ii. Specific selection by the antimicrobialiii. Genetic inheritance of the resistance trait iv. Adaptation: a population of bacteria can now live and reproduce in the presence of the drug.ANIMAL VIRUSES: ANTIVIRAL RESISTANCE5. However, over time, that population of viruses, once susceptible to the antiviral, is now resistant.a. How can a population of viruses become resistant?  Natural selection!  Make sure to include in your explanation the following underlined key words:1. Pre-existing variations in a populationa. How do random mutations come about during replication?i. Reverse transcriptase (HIV)ii. RNA-dependent RNA polymerase (Replicase) (influenza). Genome reassortment (influenza)2. Selection by antiviral drug3. Genetic inheritance of the resistance trait4. Adaptation: a population of viruses can now live and reproduce in the presence of the drug.. Explain the difference between antigenic drift and antigenic shift for Influenza viruses.i. See this video:  https:www.khanacademy.org/partner-content/stanford-medicine/stanford-school-of-medicine/stanford-influenza/v/genetic-shift-and-driftREAL-LIFE SCENARIOS6. Use the following CDC websites to answer the questions below.  Be careful of plagiarism!!HIV:https:www.cdc.gov/hivasics/livingwithhiv/treatment.htmlAntibiotic drug resistance:https:www.cdc.gov/drugresistance/pdf/ XXXXXXXXXXpdfhttps:www.cdc.gov/antibiotic-use/do-and-dont.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fantibiotic-use%2Fcommunity%2Fabout%2Fcan-do.htmlhttps:www.cdc.gov/antibiotic-use/community/pdfs/aaw/AU_viruses-or-bacteria-Chart_508.pdfa. Your patient is HIV+ but is hesitant to take anti-HIV medications.  Inform them of i. how the HIV medications work, ii. the risks of delaying taking the medications, and iii. the benefits and cautions of treatment in preventing HIV transmission to others.  Be sure to include:  ART, Viral load, suppressed viral load, undetectable viral load, AIDS and opportunistic diseases, effect on viral load and CD4 T cell count; risks of transmission to HIV-negative sexual partners, while sharing needles for IV drug use, and from mother to baby during pregnancyirth and during eastfeeding.. Your patient is HIV+ and is having trouble sticking to their treatment plan.  i. Help them understand what drug resistance is and how taking the medicines as prescribed will help them avoid drug resistance.ii. Pick 3 of the 8 possible difficulties your patient may be experiencing (explained in the “HIV Treatment” website), describe them, and talk about how you would help your patient with those issues.c. Are the following statements True or False about antibiotic drug resistance?  If False, revise them.  To revise them, you can provide the direct quotes from the websites if you quote them and cite them.  The statements MUST be in the following order:1. ___________   Antibiotics are needed to treat the flu.2. ___________   Immunization, safe food preparation, and handwashing are the ONLY ways to      prevent infections and the spread of resistance.3. ___________   Human and animal antibiotic use is always necessary.4. ___________   Tracking can help experts develop methods to prevent resistance from      spreading.5. ___________   Appropriate and safe use of antibiotics includes using “—only when they are      needed to treat disease, and to choose the right antibiotics and to administer      them in the right way in every case.”EXTRA CREDIT:  1. How do anti-fungals work? In your answer explain:a. Why is selective toxicity a more difficult issue when treating fungal infections?. Describe how azoles and echinocandins work to inhibit fungal growth.2. How do SARS-CoV-2 antiviral medications work?  Read this article and explain how molnupiravir works.  https:www.yalemedicine.org/news/9-things-to-know-about-covid-pill

Preeti · Accepted Answer

Biology 260
Biology 260				    Model Building Exercise 02 (Version 05)
Stage 02 – Antimicrobials: Susceptibility & Resistance 
Building a model to explain a natural phenomenon
Natural Phenomenon: Antimicrobial drug resistance is an enormous global health problem.  Many bacteria and viruses were once susceptible to many different antimicrobials, but now they are becoming resistant.  How does antimicrobial drug resistance happen??
BACTERIA: ANTIMICROBIAL SUSCEPTIBILITY
Our back story: Now that a pathogenic bacterium has been transmitted to our patient by getting past our microbial control methods, has made it past the patient’s normal microbiota, has found the right environment and nutrients, has harvested energy, and has grown through binary fission, and we’ve gone from one bacterium to a population of millions of bacteria causing tissue damage and disease, our patient is given an antimicrobial.
1. Explain what a biofilm is (p.94), how it forms, and how it can protect a population of bacteria from the environment (which includes antimicrobial drugs, microbial control methods, and the immune system).
Biofilm refers to the immobile communities of microbes that are attached to the surface or found as aggregates in extracellular matrix. It composed of extracellular protein, DNA etc. that helps the bacteria to tolerate harsh conditions and provides resistant against the antibacterial drugs. The common examples where biofilms can be reported are Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis etc.
 The synthesis of Biofilm requires three different stages:
a. Cell attachment to the substrate or surface
b. Adhesion
c. Growth
 Bacteria lives in these biofilms that are built on abiotic surfaces as well as biotic surfaces such as roots.   It is difficult to kill those bacteria which lives inside the biofilms.
Glycocalyx is an integral part of the biofilms and it prevents the antibiotics from reaching to their respective targets [1]. It also helps in the protection of immune system. Enzyme-mediated resistance, metabolic reactions that are occurring inside biofilms, etc. increases antibiotic resistance of biofilm [2].
2. What does it mean for a population of bacteria to be susceptible to a drug?
Susceptible to a drug means that the antibiotic is effective against the bacteria, means the bacteria can’t grow in the presence of that drug.  
	Table 1.  List of antibacterial drug classes
	i. Beta-lactam drugs (penicillins, cephalosporins, carbapenems, monobactams) 
	ii. Glycopeptide drugs
	iii. Bacitracin
	iv. Protein synthesis inhibitors (aminoglycosides, tetracyclines, glycylcyclines, macrolides, chloramphenicol, lincosamides, oxazolidonones, pleuromutilins, streptogramins)
	v. Fluoroquinolones
	vi. Rifamycins
	vii. Metronidazole
	viii. Trimethoprims + Sulfonamides
a. For each class of antimicrobial above, describe 
i. the cell synthesis process that it inhibits (cell wall synthesis, protein synthesis, nucleic acid synthesis, biosynthesis) 
There are mainly three targets that is targeted by antibiotics:
1. Cell wall
2.  Nucleic acid and,
3.  the machinery that is involved in protein synthesis
The first three classes of drugs i.e., Beta-lactam drugs, Glycopeptide drugs and Bacitracin inhibit the cell wall synthesis of bacteria. The protein inhibiting drugs mainly targets the 70s ribosomes by targeting the formation of 30s initiation complex, elongation of ribosomes. Fluoroquinolones and Rifamycin target nucleic acid synthesis. Metronidazole targets the double helical structure of DNA and breaks the strand ultimately targeting the protein synthesis and hence causing the death of the microbe. Trimethoprims and Sulfonamides targets the folic acid synthesis.
ii. the target of the class of drugs (what protein or molecule does it bind to?), 
	Beta-lactam drugs (penicillins, cephalosporins, carbapenems, monobactams) 
	Inhibits peptidoglycan synthesis by inhibiting glycan chains cross-linking
	Glycopeptide drugs
	Peptidoglycan synthesis, by binding to the chain of NAM which blocks cross-linking
	Bacitracin
	Peptidoglycan synthesis
	Protein synthesis inhibitors (aminoglycosides, tetracyclines, glycylcyclines, macrolides, chloramphenicol, lincosamides, oxazolidonones, pleuromutilins, streptogramins)
	Formation of 30s complex, Ribosome elongation, 
	Fluoroquinolones
	DNA
	Rifamycins
	RNA
	Metronidazole
	DNA double helix
	Trimethoprims + Sulfonamides
	Folic acid synthesis
iii. where in the cell you would find that target? 
There are mainly three targets that is targeted by antibiotics, cell wall, nucleic acid and the machinery that is involved in the protein synthesis. Hence the target can be the outer layer of the bacteria or can be found in the cytoplasm of the bacteria.
iv. how this class of antimicrobials kill or inhibit bacteria, and
Beta-lactam drugs, Glycopeptide drugs and Bacitracin inhibit the cell wall synthesis of bacteria. The protein inhibiting drugs mainly targets the 70s ribosomes by targeting the formation of 30s initiation complex, elongation of ribosomes. Fluoroquinolones and Rifamycin target nucleic acid synthesis. Metronidazole targets the double helical structure of DNA and breaks the strand ultimately targeting the protein synthesis and hence causing the death of the microbe. Trimethoprims and Sulfonamides targets the folic acid synthesis.
v. how this class of antimicrobials exhibits selective toxicity.
The selective toxicity of the drug can be found by targeting only those targets which are solely found in the bacteria and won’t cause any harm to the animal or human host.
b. Many of these antimicrobials work through competitive or noncompetitive inhibition of the specific enzyme or molecule (a target) that is required for these synthesis pathways.  Describe how competitive and non-competitive inhibition work (review from Bio160).
The main difference between the competitive and non-competitive inhibitor is the binding site of the inhibitor. The competitive inhibitor binds to the active site of the enzyme and hence, inhibits its activity while the non-competitive inhibits the enzymatic activity by binding at the site which is not the active site of the enzyme.
c. Draw or copy and paste a Gram-positive and a Gram-negative cell wall and cytoplasmic membrane (See Figure 3.32 and 3.33).  Make sure to include all the structures and label each structure.
i. On those pictures: 
1. Name, draw, and label the targets of the antimicrobials in Table 2 below 
Shirly Berezin et al [3]
2. Draw and explain how these drugs (Table 2) gain access to their targets.
	Table 2.  List of antimicrobials
	ertapenem
	azithromycin
	co-trimoxazole
	Table 2.  List of antimicrobials
	Target
	ertapenem
	Cell wall synthesis
	azithromycin
	Protein synthesis
	co-trimoxazole
	Folic acid metabolism
Ertapenem binds with the penicillin binding protein of the cell wall and inhibits its synthesis.
Azithromycin inhibits the translation of mRNA (refer to above mentioned figure)
Co-trimoxazole blocks the folic acid enzymes in the synthesis pathway.
 
ANIMAL VIRUSES: ANTIMICROBIAL SUSCEPTIBILITY
How do animal viruses replicate?  How can we use this information to explain how antiviral drugs work?  In your answer explain how the following two viruses replicate:
The animal viruses first get attached to the cell membrane of the animal cell and then injects its genetic material (DNA or RNA) inside the cytoplasm of the animal cell. There by using the host cell machinery the genome of virus replicates and make multiple copies of itself. They use host machinery for packaging of the virion. Then, by killing the cell (lytic phase) or budding off the cell membrane (lysogeny), the newly synthesised viruses released outside the cell.
The antiviral drugs can target the attachment of the virus to the cell membrane of the animal cell or they can also target the viral enzymes such as protease, methyltransferase or RNA-dependent RNA polymerase of the virus, which can ultimately stop its replication. For example, methyltransferase enzyme provides stability to the mRNA of positive-stranded RNA viruses by capping its mRNA. Hence, if a drug targets the methyltransferase enzyme, then the viral RNA won’t be stable and the uncapped RNA will be destroyed by host immune system.
Replication cycle of HIV:
HIV enters the hos body and gets fused with T-cells and uses the host machinery. The reverse transcriptase enzyme of the virus helps to produce complementary DNA of the virus using RNA genome of the virus as template. The host machinery will help to produce more viral RNA copies by transcribing the HIV cDNA. The new viral RNA and proteins forms immature HIV and this immature HIV gets released from the cell. The HIV protease protein is used in the polyprotein processing to form a mature HIV virus.
Replication cycle of Influenza virus:
After entering the host body, Influenza virus binds with the host cell using hemagglutinin (HA) protein. After cleavage of HA, the virus is transferred into the host cell using endocytosis. The viral genome and proteins is then released into the cytoplasm of the cell. The influenza virus is a negative-stranded RNA virus hence, first the negative strand is first used as a template to produce a positive-stranded RNA, which is then translated into the viral proteins. It is used as a template to create more copies of viral genome and then the viral genome and proteins is assembled into the virions and released out of the cell. 
	Table 3.

Biology 260 Biology 260 Model Building Exercise 02 (Version 05) Stage 02 – Antimicrobials: Susceptibility & Resistance Building a model to explain a natural phenomenon Natural Phenomenon:...

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