Aminoglycosides

Introduction:

Aminoglycosides comprise a complex group of drugs derived from soil Actinomycetes in the genera Streptomyces and Micromonospora that impairs ribosome function and has antibiotic potential. 

Examples includes Streptomycin, gentamicin, tobramycin, and, amikacin.

Mode of Action:

This complex group of drugs inserts itself on sites on the 30S ribosomal subunit of the prokaryotes and causes the misreading of the mRNA, eventually leading to abnormal proteins. 

Figure: Site of inhibition on the prokaryotic ribosome by the drug aminoglycoside, which has a general effect of blocking the protein synthesis. The blockage action is indicated by X. 

Structure of the drug:

The aminoglycoside class of drugs comprises one or more amino sugars and an aminocyclitol ring, a 6-carbon cyclic ring. 

Figure: The structure of an aminoglycoside: Streptomycin.

 Coloured portions of the molecule are found in all members of this drug class. 

Subgroups and Uses of Aminoglycosides:

The aminoglycoside group of drugs possesses a relatively broad antimicrobial spectrum since they inhibit the synthesis of prokaryotic proteins by binding to one of the ribosomal subunits. Therefore, this group of drugs is mostly used to treat infections generally caused by aerobic gram-negative rods and gram-positive bacteria. 

Streptomycin is one of the oldest known drugs. However, it is gradually being replaced by newer forms of drugs that possess less mammalian toxicity. However, even today, Streptomycin is considered an effective antituberculosis agent and an antibiotic of choice for treating bubonic plague and tularaemia. 

Gentamicin is less toxic and is widely administered for infections caused by gram-negative rods such as Escherichia, Pseudomonas, Salmonella, and Shigella. 

Two relatively new aminoglycosides; amikacin, and tobramycin are also used for gram-negative infections, with tobramycin especially useful for treating Pseudomonas infections in cystic fibrosis patients.

Antimicrobial Resistance 

Since this complex group of drugs works by blocking the protein synthesis in prokaryotes, the microbes usually circumvent these drugs by altering the nature of the protein target. Bacteria can thus become resistant to aminoglycosides when point mutations in ribosomal proteins arise.

Drug toxicity:

Aminoglycosides can directly act on the brain and cause seizures. In addition, this group of drugs may damage nerves (very commonly, the eighth cranial nerve), leading to dizziness, deafness, or motor and sensory disturbances. 

Aminoglycosides such as gentamicin are nephrotoxic and are poorly cleared by damaged kidneys. 

Note: The intake of other drugs must be carefully scrutinized because incompatibilities can result in increased toxicity or failure of one or more of the drugs. For example, the combination of aminoglycosides and cephalosporins increases nephrotoxic effects. 

Article by- SAMPRATI PAREKH (MSIWM049)

References: Talaros Foundations in Microbiology – 8^thEdition 

ANTIBIOTICS

BY: SAI MANOGNA (MSIWM013)

Introduction :

Antibiotics are used in the treatment of preventing bacterial infection. They work by destroying or stopping bacteria from reproducing and spreading. Antibiotics do not work against respiratory infections like the common cold, flu, most coughs, and sore throats. The immune system can also cleanse several mild bacterial infections without using antibiotics, but they are not regularly prescribed. Antibiotics must be administered and appropriately taken to help prevent the development of antibiotic resistance.

Antibiotics, also known as antibacterials, are medicines that destroy or slow bacterial growth. In 1929, Alexander Fleming identified penicillin, the first antibiotic compound. Penicillins, Aminoglycosides, Quinolones,  Macrolides, Sulfonamides, Cephalosporins, Carbapenems, and Tetracyclines are common antibiotics. General antibiotic prescription principles are used: first-line antibiotics, reserve wide-spectrum antibiotics only for indicated conditions, prescribe antibiotics for bacterial infections if symptoms are severe or extreme.

Antibiotics can be given in several ways:

Oral antibiotics: pills, capsules, or a liquid drink to treat most cases of mild to severe body infections

Topical antibiotics: creams, lotions, sprays, or drops sometimes used to treat skin infections

Antibiotic injections: these may be administered or infused directly into the blood or muscle and are typically reserved for more extreme infections

Types Of Antibiotics :

There are hundreds of different forms of antibiotics: but most can be grouped into six classes. They are listed below.

Penicillins (such as penicillin and amoxicillin)

Cephalosporins (such as cephalexin)

Aminoglycosides (such as gentamicin and tobramycin)

Tetracyclines (such as tetracycline and doxycycline)

Macrolides (such as erythromycin and clarithromycin)

Fluoroquinolones (such as ciprofloxacin and levofloxacin)

1. Penicillins :

a. Penicillins are an antibiotic of penicillium fungi. An antibiotic is a drug that prevents bacteria ‘s growth or destroys.

b. The 1928 accident discovered penicillin G (also called benzylpenicillin). Alexander Fleming, a Scottish physicist, developed a form of bacteria called Staphylococcus Aureus on an uncovered petri dish when infected with mold spores. He noticed the bacteria near the mold dying. He isolated the mold material that destroyed the bacteria and named it penicillin.

c. Natural penicillins (penicillin G, penicillin V) are active only against gram-positive bacteria. Penicillin V is acid-resistant than penicillin G

d. Penicillin V was isolated from the same mold. All other penicillins are semi-synthetic, made by changing the structure of the original naturally occurring penicillins.

e. Classic semi-synthetic penicillins include ampicillin and oxacillin. These have some degree of beta-lactamase resistance and are effective against some gram-negative bacteria.

f. Most bacteria can be categorized as gram-positive or gram-negative based on variations in their cell wall structure, which can be microscopically differentiated using the dye form.

g. One of the main distinctions is that gram-positive bacteria are more susceptible to antibiotics, whereas gram-negative bacteria are more antibiotic-resistant.

Penicillins such as piperacillin and ticarcillin are penicillins with additional activity against some hard-to-kill types of gram-negative bacteria (Pseudomonas, Klebsiella, and Enterococcus).

A beta-lactamase inhibitor incorporates certain penicillins. A beta-lactamase inhibitor blocks beta-lactamase enzyme activity but tends to have little antibiotic activity. Some penicillins (like oxacillin, dicloxacillin, and nafcillin) are naturally resistant to certain beta-lactamases and are called penicillin-resistant. Others, such as amoxicillin, ampicillin, and piperacillin, may be extended by combining them with a beta-lactamase inhibitor. Clavulanate, sulbactam, and tazobactam all inhibit beta-lactamase.

Penicillins function by preventing bacterial cell wall cross-linking of amino acid chains. This does not affect pre-existing bacteria, but new bacterial cells have fragile cell walls that rupture easily.

Uses: Penicillins are used to treat

 i. Dental abscess

ii. Ear infections

iii. Gonorrhea

iv. Pneumonia

v. Rheumatic fever

vi. Skin infections

vii. Urinary tract infections

2. Tetracyclines:

a. The first tetracyclines were derived from Streptomyces bacteria in the 1940s.

b. These can be used to treat infections caused by susceptible microorganisms such as gram-positive and gram-negative bacteria, chlamydiae, mycoplasma, protozoans and rickettsiae.

c. Tetracyclines inhibit protein synthesis in microbial RNA (an essential molecule for DNA messenger). They are mainly bacteriostatic, thereby stopping bacteria from spreading but not necessarily killing them.

d. Although tetracyclines all function the same way, there are variations between the four tetracyclines (demeclocycline, doxycycline, minocycline, and tetracycline).

Doxycycline is the most commonly used tetracycline. It causes photosensitivity or binds to calcium, causing dental discoloration or bone growth retardation.

Uses: Tetracyclines are used to treat

i. Malaria

ii. Treatment of moderate to severe acne

iii. Anthrax

iv. Infections of an eye, gastrointestinal tract, respiratory tract, and skin

v. infections caused by Campylobacter, Yersinia pestis, Vibrio cholerae, Chlamydiae, and other atypical organisms

3. Cephalosporins :

a. Cephalosporins are a broad group of Acremonium-derived antibiotics (formerly Cephalosporium).

b. Cephalosporins are bactericidal (kill bacteria), similar to penicillins. They bind and block enzyme activity responsible for producing peptidoglycan, an essential bacterial cell wall component. They are called broad-spectrum antibiotics because they affect a wide range of bacteria.

c. Since the first cephalosporin was discovered in 1945; scientists have refined cephalosporin structure to make it more effective against broader bacteria.

d. Whenever structure changes, a new “generation” of cephalosporins is made. There are five generations of cephalosporins.

e. Both cephalosporins begin with cef, ceph, or kef. Notice that this classification scheme is not used consistently across countries.

Currently, there are five “generations” of cephalosporins, each generation varying slightly in their antibacterial range ( i.e., how successful they are in destroying certain types of bacteria). There are variations in administration (such as oral or intravenous administration), absorption, excretion, and how long the body’s cephalosporin activity lasts.

First-generation :

First-generation cephalosporins are the first group of cephalosporins found. Their optimal activity against gram-positive bacteria like staphylococci and streptococci. They have little anti-gram-negative activity.

Second-generation :

Second-generation cephalosporins are more active against gram-negative bacteria, with less gram-positive bacteria.

Third-generation :

The second-generation cephalosporins preceded third-generation cephalosporins. No third-generation cephalosporin treats all scenarios of infectious disease.

Cefotaxime and ceftizoxime provide the best gram-positive coverage of all third-generation agents; ceftazidime and cefoperazone are unique in providing antipseudomonal coverage.

Fourth generation :

Fourth-generation cephalosporins are structurally similar to third-generation cephalosporins. However, they have a different ammonium group that enables them to penetrate the outer membrane of gram-negative bacteria, enhancing their activity. They are also active against β-lactamase generating Enterobacteriaceae that may inactivate cephalosporins of third-generation.

Some fourth-generation cephalosporins have excellent activity against gram-positive bacteria such as staphylococci, penicillin-resistant pneumococci, and streptococci group viridans.

Fifth-generation :

Ceftaroline is currently the only cephalosporin of next-generation available in the U.S. It acts against methicillin-resistant Staphylococcus aureus ( MRSA) and gram-positive bacteria. It also retains later-generation cephalosporin activity and works against susceptible gram-negative bacteria.

Uses: Cephalosporins are used to treat

i. Bone, skin, and ear infections

ii. Urinary tract infections

4. Quinolines:

a. Quinolones are antibiotics that kill or inhibit bacteria.

b. Five separate quinolone groups exist. Another antibiotic class, called fluoroquinolones, was derived from quinolones by modifying their fluorine structure.

c. Quinolones and fluoroquinolones have some common and some differences, such as against which organisms they work.

d. Quinolones and fluoroquinolones affect the role of topoisomerase IV and DNA gyrase so that they can no longer fix DNA or assist in its development.

e. Quinolones and fluoroquinolones vary in their action against the two enzymes produced by bacteria, topoisomerase IV and DNA gyrase.

f. Those more active against topoisomerase IV have more effect on gram-positive bacteria; those active against DNA gyrase are more active against gram-negative bacteria.

g. Quinolones and fluoroquinolones also vary in body absorption, metabolization, and excretion.

Uses: Quinolines are used to treat

i. Unusual infections such as plague and anthrax

5. Macrolides :

a. Macrolide derivatives are either a macrolide or macrolide-related antibiotics.

b. Macrolides are antibiotics found in streptomycetes.

c. They are natural lactones with a complete ring of 14-20 atoms.

d. Macrolides bind to the bacterial ribosome 50S subunit and inhibit ribosomal translocation, leading to bacterial protein synthesis inhibition.

e. Their action is primarily bacteriostatic, but at high concentrations, depending on the type of microorganism.

Uses: Macrolides are used to treat uncomplicated skin infections, pneumonia, pertussis, and other susceptible infections.

6. Aminoglycosides :

a. Aminoglycosides are a class of antibiotics used primarily to treat aerobic gram-negative bacilli infections

b. These are effective against other bacteria such as Mycobacterium tuberculosis Staphylococci. They are often used with other antibiotics.

c. Aminoglycosides can function by inhibiting protein synthesis within bacteria.

d. Bacteria kill rates are increased when higher aminoglycoside concentrations are present.

e. Kidney impairment and hearing loss are the most common side effects of aminoglycosides.

f. Aminoglycosides are usually used when other antibiotics are contraindicated or ineffective.

g. Aminoglycosides are not well absorbed by mouth, so healthcare workers need to be injected.

Others :

a. Carbapenems

These injectable beta-lactam antibiotics have a wide range of bacteria-killing ability. They can be used for mild to life-threatening bacterial infections such as stomach infections, pneumonia, kidney infections, hospital-acquired multidrug-resistant infections, and many other severe bacterial diseases. They are often saved or used as “last-line” agents to help prevent resistance.

b. Antibiotic – Glycopeptide

Members can be used to treat methicillin-resistant staphylococcus aureus (MRSA) infections, complicated skin infections, C. Difficult-associated diarrhea, enterococcal infections such as beta-lactam-resistant endocarditis, and other antibiotics.

c. Sulphonamides

Sulfonamides function against some gram-positive and many gram-negative bacteria, but resistance is widespread. Sulfonamide uses include urinary tract infections ( UTIs), pneumonia treatment or prevention, or ear infections (otitis media).

d. Lincomycins :

Lincomycins have activity against gram-positive aerobes and anaerobes, as well as some gram-negative anaerobes. Lincomycin derivatives may be used to treat severe infections such as pelvic inflammatory disease, lower respiratory tract infections, intra-abdominal infections, and bone and joint infections. Some forms are also used topically to treat acne.

Antimicrobial resistance:

Overuse of antibiotics in recent years means they become less successful, and “superbugs” have arisen. There are bacterial strains that withstand several different forms of antibiotics, including:

Methicillin Staphylococcus aureus (MRSA)

Clostridium difficile (CD)

Multidrug – resistant tuberculosis (MDR-TB) bacteria

Carbapenemase Enterobacteriaceae (CPE)

These infections can be extreme and challenging to manage and are rapidly causing disability and death worldwide.

Antibiotic side-effects

Like any drug, antibiotics can cause side-effects. Most antibiotics do not cause problems if adequately used, and severe side effects are rare.

The most popular side-effects are:

Bloating, indigestion, diarrhea

Some people may be allergic to antibiotics, particularly penicillin, and a form called cephalosporins. This may lead to an extreme allergic reaction (anaphylaxis), a medical emergency in scarce circumstances.