Antibiotics: Protein Synthesis Inhibitors

This bedroom is soooo pretty, this colour palette is everything.

Antimicrobial Agents - Inhibition of DNA and Protein Synthesis

Bacterial chromosome replication

DNA replication

Bacterial Topoisomerases 

maintain DNA in appropriate state of supercoiling 

cut and reseal DNA

DNA gyrase (topoisomerase II) introduces negative supercoils 

Topoisomerase IV decatenates circular chromosomes 

these are the targets of the quinolone antibacterial agents 

Quinolones

bind to bacterial DNA gyrase and topoisomerase IV after DNA strand breakage 

prevent resealing of DNA 

disrupt DNA replication and repair 

bactericidal (kill bacteria)

Fluoroquinolone is particularly useful against

Gram +ves: Staphylococcus aureus, streptococci 

Gram -ves: Enterobacteriacea; Pseudomonas aeruginosa 

Anaerobes: e.g. Bacteroides fragilis 

many applications e.g. UTIs, prostatitis, gastroenteritis, STIs 

Adverse effects

Relatively well tolerated

GI upset in ~ 5% of patients 

allergic reactions (rash, photosensitivity) in 1 - 2% of patients 

Inhibition of Bacterial Protein Synthesis 

Macrolides 

in 1952: Erythromycin was isolated as the first macrolide (Streptomyces erythreus) 

Newer macrolides: clarithromycin, azithromycin 

Structurally they consist of a lactone ring (14- to 16-membered) + two attached deoxy sugars 

Mode of action 

bind reversibly to bacterial 50S ribosomal subunit 

causes growing peptide chain to dissociate from ribosome → inhibiting protein synthesis 

bacteriostatic (stops reproduction)

Macrolides’ spectrum of activity

good antistaphylococcal and antistreptococcal activity 

treatment of respiratory & soft tissue infections and sensitive intracellular pathogens • e.g. Chlamydia, Legionella 

Adverse effects

Generally well tolerated

nausea 

vomiting 

diarrhoea 

rash 

Aminoglycosides

large family of antibiotics produced by various species of Streptomyces (“mycin”) and Micromonospora (“micin”) 

include: streptomycin, neomycin, kanamycin, gentamicins, tobramycin 

Structure = linked ring system composed of aminosugars and an aminosubstituted cyclic polyalcohol 

Mode of action of aminoglycosides

Bind irreversibly to 30S ribosomal subunit 

disrupt elongation of nascent peptide chain 

translational inaccuracy → defective proteins 

bactericidal 

Spectrum of activity 

broad spectrum; mainly aerobic G-ve bacilli (e.g. P. aeruginosa) 

used to treat serious nosocomial infections (hospital acquired infections)

First TB antibiotic

Used for cystic fibrosis 

Adverse effects

all aminoglycosides have low Therapeutic Index (only a small amount needed to become toxic)

renal damage, ototoxicity, loss of balance, nausea 

Cryptosporidium

Cryptosporidium is a microscopic parasite that causes the diarrhoeal disease cryptosporidiosis. Both the parasite and the disease are commonly known as “Crypto.”

The parasite is protected by an outer shell (oocyst)

Allows survival outside the body for long periods of time 

Very tolerant to chlorine disinfection.

Water is the most common form of spread

Poses serious risk to immunocompromised individuals, eg AIDS; cancer and transplant patients who are taking certain immunosuppressive drugs. 

Symptoms

Symptoms of cryptosporidiosis generally begin 2 to 10 days (average 7 days) after infection. 

Watery diarrhea

Stomach cramps or pain

Dehydration

Nausea

Vomiting

Fever

Weight loss

Some people with Crypto will have no symptoms at all.

Symptoms usually last about 1 to 2 weeks (with a range of a few days to 4 or more weeks) in persons with healthy immune systems. Occasionally, people may experience a recurrence of symptoms after a brief period of recovery before the illness ends. Symptoms can come and go for up to 30 days.

In immunocompromised persons Cryptosporidium infections could possibly affect other areas of the digestive tract or the respiratory tract.

Diagnosis & Detection

Cryptosporidium oocysts in a modified acid-fast stain. (CDC Photo; DPDx)

Examination of stool samples. 

Detection can be difficult - several stool samples over several days.

acid-fast staining, direct fluorescent antibody [DFA] , and/or enzyme immunoassays 

Molecular methods (e.g., polymerase chain reaction – PCR) are increasingly used in reference diagnostic labs,

Treatment

Most people who have healthy immune systems will recover without treatment. Young children and pregnant women may be more susceptible to dehydration resulting from diarrhoea. 

For those persons with AIDS, anti-retroviral therapy (improves the immune status) will also decrease or eliminate symptoms of cryptosporidiosis. However, even if symptoms disappear, cryptosporidiosis is often not curable and the symptoms may return if the immune status worsens.

Cryptosporidium and AIDS

Advanced immunosuppression — typically CD4 T lymphocyte cell (CD4) counts of <100 cells/µL — is associated with the greatest risk for prolonged, severe, or extraintestinal cryptosporidiosis. 

The three species that most commonly infect humans are Cryptosporidium hominis, Cryptosporidium parvum, and Cryptosporidium meleagridis. Infections are usually caused by one species, but a mixed infection is possible.

Up to 74% of diarrhoea stools in AIDS patients demonstrating the organism in less developed countries where potent antiretroviral therapy  is not widely available, 

cryptosporidiosis has decreased and occurs at an incidence of <1 case per 1000 person-years in patients with AIDS.4 Infection occurs through ingestion of Cryptosporidium oocysts. Viable oocysts in feces can be transmitted directly through contact with infected humans or animals, particularly those with diarrhea. Oocysts can contaminate recreational water sources such as swimming pools and lakes, and public water supplies and may persist despite standard chlorination (see Appendix: Food and Water-Related Exposures). Person-to-person transmission is common, especially among sexually active men who have sex with men.

Fever is present in approximately one-third of patients and malabsorption is common. 

The epithelium of the biliary tract and the pancreatic duct can be infected with Cryptosporidium, leading to sclerosing cholangitis and to pancreatitis secondary to papillary stenosis, 

Pulmonary infections also have been reported, and may be under-recognized.

Treatment 

ART with immune restoration to a CD4 count >100 cells/µL usually leads to resolution

Treatment of diarrhoea with anti-motility agents (AIII) may be necessary. 

Patients with biliary tract involvement may require endoscopic retrograde choledocoduodenoscopy for diagnosis. 

Immune reconstitution inflammatory syndrome (IRIS) has not been described in association with treatment of cryptosporidiosis.

No pharmacologic interventions are known to be effective in preventing the recurrence of cryptosporidiosis.

No therapy has been shown to be effective without ART. 

My assistant

Medically Important Bacteria: Clasification

https://www.instagram.com/studydiaryofamedstudent/

-28/11/17-

Had cramps so spent the day writing up microbiology notes whilst hunched over my hot water bottle. The lecture on vaccine design is 7 pages long and now I can hand cramp to my list of ailments…

Clostridium perfringes

Nagler reaction: C. perfringens phospholipase causes turbidity around the colonies on egg-yolk medium. Inhibited by specific antiserum.

Anaerobic stormy fermetantion in milk media

Food poisoning strains produce heat resistant spores.

Type A spores producing gas gangrene are inactivated by heat quickly.