Antimicrobials; antibacterials, antifungals, antiprotozoans, antivirals,

and antihelminthics 4

Inhibitors of Protein Synthesis

Tetracyclines Broad spectrum

− Interferes with tRNA attachment

Figure 20.11

Inhibitors of Protein Synthesis

Tetracyclines produced by Streptomyces Broad spectrum; gram (+) & (-) mycoplasma, rickettsias & chlamydias (penetrate into body tissue ) Oxytetracycline (Terramycin), chlorotetracycline (Aureomycin), semisynthetics

(doxycycline, minocycline; longer retention time) For urinary tract infections, mycoplasmal pneumonia, chlamydial & rickettsial

infections. alternative for syphilis & gonorrhea Suppress normal microbiota; causing GI upset (C. difficle) & superinfection (C.

albicans) Not advised for children (brownish teeth), for pregnant women (liver damage) The most common antibiotic added to animal feed

Macrolides: macrocyclic lactone ring −Gram-positives − Binds 50S; prevents translocation

Inhibitors of Protein Synthesis

Figure 20.12

Inhibitors of Protein Synthesis Erythromycin

Gram (+) (not able to penetrate gram (-))

Similar spectrum with penicillin (an alternative for penicillin)

Oral administration (penicillin substituent for children’s streptococcal &

staphylococcal infections)

Legionellosis, mycoplasmal pneumonia

Azithromycin & clarithromycin; broader spectrum & better

penetration of tissues (important for intracellular pathogens,

chlamydia)

Ketolides (telithromycin; Ketek); semisynthetic, developed for

macrolides-resistant bacteria. Significant restriction in use due to

toxicity Figure 20.12

Inhibitors of Protein Synthesis

Streptogramins Gram-positives

− Binds 50S subunit; inhibits translation

Streptogramins; distantly related to macrolides For the vancomycin-resistance Gram (+), binds 50S subunit, inhibits translation Synercid; synergistic combination of two cyclic peptides,

quinupristin (block later step of protein synthesis) & dalfopristin (block early step of protein synthesis). Effective to broad range of antibiotic-resistant gram (+) bacteria. Expensive & adverse side effects.

Quinupristin/dalfopristin Pristinamycin Virginiamycin NXL 103, an experimental streptogramin in clinical trials for

the treatment of respiratory tract infections.

Inhibitors of Protein Synthesis

Inhibitors of Protein Synthesis

Oxazolidinones totally synthetic For Gram (+), no usefulness against Gram (-), but active

against certain enterococci that are not sensitive to Synercid

Developed for vancomycin-resistant bacteria. Binds 50S subunit; prevents formation of 70S ribosome Slow development of resistance. Approved in 2001. New antibiotic class approved in 25

years. bacteriostatic agent, not bacteriocidal

Linezolid (Zyvox); for MRSA

− first commercially available 1,3-oxazolidinone antibiotic

− marketed by Pfizer under the trade names Zyvox (in USA, UK, Australia),

Zyvoxid (in Europe), and Zyvoxam (in Canada and Mexico).

− Generics are also available, such as Linospan, Arlin, and Linospan.

− Bacterial resistance to linezolid has remained very low since it was first

detected in 1999, although it may be increasing.

− For short periods, relatively safe, it can be used in patients of all ages and

in people with liver disease or poor kidney function. Common side effects

(more than 1% of people taking linezolid) include diarrhea (3–11%),

headache (1–11%), nausea (3–10%), vomiting (1–4%), rash (2%),

constipation (2%), altered taste perception (1–2%), and discoloration of the

tongue (0.2–1%).

− but in long term use, it has serious adverse effects. linezolid can cause bone marrow

suppression and low platelet counts, particularly when used for more than two weeks.

If used for longer periods still, it may cause sometimes irreversible chemotherapy-

induced peripheral neuropathy and optic nerve damage, and lactic acidosis (a buildup

of lactic acid in the body), all most likely due to mitochondrial toxicity

− Fungal infections such as thrush and vaginal candidiasis may also occur as by

suppressing normal microbiota (so-called antibiotic candidiasis). Like other antibiotics,

linezolid has been associated with Clostridium difficile-associated diarrhea (CDAD),

but C. difficile appears to be susceptible to linezolid in vitro, and linezolid was even

considered as a possible treatment for CDAD.

− Less common (and potentially more serious) adverse effects include allergic

reactions, pancreatitis, and elevated transaminases, which may be a sign of liver

damage.

− very expensive, costing approximately US$100 per pill in USA. Nonetheless, it

appears to be more cost-effective than comparable antibiotics, such as vancomycin,

mostly because of the possibility of switching from intravenous to oral administration.

Glycylcyclnes Pleuromutilins

Injury to the Plasma Membrane

Isoniazid (anti-tuberclosis drug), triclosan (disinfectant),

platensimycin, polymixin B, and antimicrobial peptides

Especially significant because it represents another rare

example of a new chemical class of antibiotic to appear in

the last 40 years

another weapon to use against the treat of MRSA

Platensimycin −a metabolite of Streptomyces platensis,

−an example of a unique structural class of natural antibiotics for a

breakthrough in recent antibiotic research due to its unique functional

pattern and significant antibacterial activity.

−act by blocking enzymes involved in the condensation steps in fatty acid

biosynthesis, which Gram-positive bacteria need to biosynthesise cell

membranes (β-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B)).

−Other enzymes in this pathway have similarly been proven antibiotic targets

for example FabI, the enoyl-ACP (acyl carrier protein) reductase, that is

inhibited by isoniazid and related compounds and the antiseptic agent

triclosan.

Injury to the Plasma Membrane

Polymyxin B Topical Combined with bacitracin and neomycin in over-the-counter preparation Seldom used except for topical agents Effective against gram (-) & Pseudomonas Combined with bacitracin and neomycin in antiseptic ointments without

prescription

Antimicrobial peptides; not approved yet, but promising future chemotherapeutic agents. Defensin (from human), magainin (from frog), Nisin (resemble magainin)

Lipopeptides: recently developed Daptomycin: Produced by Streptomycetes

− Against Gram (+) − Structural damage on membrane followed by arrest of the

synthesis of DNA, RNA, and proteins − Approved for treatment of MRSA infection