Antimicrobial Agents in the Treatment of Infectious Disease (2023)

Antimicrobial Agents in the Treatment of Infectious Disease
(page 3)(This chapter has 6 pages)© Kenneth Todar, PhD

Antimicrobial Agents Used in the TreatmentofInfectious Disease Examination of the foregoing table reveals that there are ahandfulof fundamental ways that antibacterial antibiotics work as therapeuticagents. Recall that the target of an antibiotic should be unique to thebacterium and not found, or not accessible to the antibiotic, in thepatient. These are the most important targets in bacteria that havebeen exploited so far.

1. Attack bacterial cell wall synthesis. Bacteria have murein in theircell walls, not found in the host, and murein (peptidoglycan) isessential to the viability of the bacterium.

2. Interfere with protein synthesis. Attack is almost always ate thelevel of translation using 70S ribosomes in the translation machinery.70S cytoplasmic ribosomes are absent in eucaryotes.

3. Interference with nucleic acid synthesis (RNA and DNA), whichexploits differences between RNA polymerases and DNA replicationstrategies in bacteria and eucaryotes.

4. Inhibition of an essential metabolic pathway that exists in thebacterium but does not exist in the host. This is usually brought aboutthrough the use of competitive chemical analogs for bacterial enzymaticreactions.

5. Membrane inhibition or disruption doesn't work too well because ofthe similarities between eucaryotic and bacterial membranes. However,the outer membrane of Gram-negative bacteria is a reasonable point ofattack and some membrane inhibitors are included in the discussionbelow.

Cell wall synthesis inhibitors

Cell wall synthesis inhibitors generally inhibit some step in thesynthesis of bacterial peptidoglycan. They exert theirselective toxicity against bacteria because humans cells lack cellwalls.

Beta lactam antibiotics. Chemically, these antibioticscontain a4-membered beta lactam ring. They are the products of two genera offungi, Penicillium and Cephalosporium, and arecorrespondingly represented by the penicillins and cephalosporins.

Chemical structures of somebeta-lactam antibiotics. Clockwise: penicillin, cephalosporin,monobactam, carbapenem. Note the characteristic structure of the betalactam ring.

The beta lactam antibiotics are stereochemically related toD-alanyl-D-alanine, which is a substrate for the last step inpeptidoglycan synthesis, the final cross-linking between betweenpeptide side chains. Penicillins bind toand inhibit the carboxypeptidase and transpeptidase enzymes that arerequired for this step in peptidoglycan biosynthesis. Beta lactamantibiotics are bactericidal and require that cells beactively growing in order to exert their toxicity.

Different beta lactams differ in their spectrum of activity andtheir effecton Gram-negative rods, as well as their toxicity, stability in thehumanbody, rate of clearance from blood, whether they can be taken orally,abilityto cross the blood-brain barrier, and susceptibility to bacterialbeta-lactamases.

Natural penicillins, such as penicillin G or penicillinV (benzyl penicillin), are produced by fermentation of Penicilliumchrysogenum.They are effective against streptococci, gonococci andstaphylococci, except where resistance has developed. They areconsidered narrow spectrum since they are not effective againstGram-negative rods.

PenicillinG(Benzylpenicillin) is typically given by parenteral administrationbecause it is unstable in the acid of the stomach. However, thisachieves higher tissue concentrations than orally-administeredpenicillins and this increases its antibacterial potential."PenG" may be used in treatment of bacterial endocarditis, gonorrhea,syphilis, meningitis, and pneumonia.

Semisynthetic penicillins first appeared in 1959. A moldproduces the main part of the molecule (6-aminopenicillanic acid),whichcan be modified chemically by the addition of side chains. Many ofthese compounds have been developed to have distinct benefits oradvantages over penicillin G, such as increased spectrum of activity(effectiveness against Gram-negative rods), resistance topenicillinase, effectiveness when administered orally, etc.; amoxicillinand ampicillin have broadened spectra against Gram-negativebacteriaand are effective orally; methicillin ispenicillinase-resistant.

The structure of calvulanicacid. Clavulanic acid is not an antibiotic. It is a beta-lactamaseinhibitor sometimes combined with semisynthetic beta lactam antibioticsto overcome resistance in bacteria that produce beta-lactamase enzymes,which otherwise inactivate the antibiotic. Most commonly it is combinedwith amoxicillin (above) as Augmentin (trade name) or the veterinarypreparation, clavamox.

Although nontoxic, penicillins occasionally cause death whenadministered to persons who are allergic to them. In the U.S. there are300 - 500 deaths annually due to penicillin allergy. In allergicindividuals the beta lactam molecule attaches to a serum protein andinitiates an IgE-mediated inflammatory response.

Cephalosporins are beta lactam antibiotics with a similarmode of action to penicillins. They are produced by species ofCephalosporium molds. The havea low toxicity and a somewhat broader spectrumthan natural penicillins. They are often used as penicillinsubstitutes against Gram-negative bacteria and in surgicalprophylaxis. They are subject to degradation by some bacterialbeta-lactamases, but they tend to be resistant to beta-lactamases from S.aureus.

Two other classes of beta lactams are the carbapenems and monobactams.The latter are particularly useful for the treatment of allergicindividuals. A person who becomes allergic to penicillin usuallybecomes allergic to the cephalosporins and the carbapenems as well.Such individuals can still be treated with the monobactams, which arestructurally different so as not to induce allergy.

Aztreonam is a synthetic monocyclic beta lactam antibiotic (amonobactam) originally isolated from the bacterium Chromobacterium violaceum. Itis not useful against Gram-positive bacteria but it has strong activityagainst a wide range of susceptible Gram-negative bacteria, including Pseudomonas aeruginosa, E. coli,Haemophilus and Klebsiella.

Bacitracin is a polypeptide antibiotic produced by Bacillusspecies. It prevents cell wall growth by inhibiting the release ofthe muropeptide subunits of peptidoglycan from the lipid carriermolecule that carries thesubunit to the outside of the membrane. Teichoic acid synthesis, whichrequiresthe same carrier, is also inhibited. Bacitracin has a high toxicitywhichprecludes its systemic use. It is present in many topical antibioticpreparations,and since it is not absorbed by the gut, it is given to "sterilize" thebowelprior to surgery.

Bacitracin is a polypeptide antibiotic produced by the licheniformisgroup of Bacillus subtilis var.Tracy. It is effective used topically, primarily against Gram-positivebacteria. It is used in ointment or cream form for topical treatment ofa variety of localized skin and eye infections, as well as for theprevention of wound infections. A popular brand name Neosporin,containsbacitracin, neomycin and polymyxin B.

Glycopeptides, such as the antibiotic vancomycin,inhibit both transglycosylation and transpeptidationreactions during peptidoglycan assembly. They bind to the muropeptidesubunit as it is transferred out of the cell cytoplasm and inhibitsubsequent polymerization reactions. Vancomycin is not effectiveagainst Gram-negative bacteria because it cannot penetrate their outermembrane. However, it has become important in clinical usage fortreatment of infections by strains of Staphylococcus aureusthat are resistant to virtually all other antibiotics (MRSA).

Vancomycinis a glycopeptide antibiotic used in the prophylaxis and treatment ofinfections caused by Gram-positive bacteria. It has traditionally beenreserved as a drug of "last resort",used only after treatment with other antibiotics had failed, althoughthe emergence of vancomycin-resistant organisms means that it isincreasingly being displaced from this role by linezolid and thecarbapenems.

Cell membrane inhibitors

These antibiotics disorganize the structure or inhibit the functionof bacterial membranes. The integrity of the cytoplasmic and outermembranes is vital to bacteria, and compounds that disorganize themembranes rapidly kill the cells. However, due to the similarities inphospholipids in eubacterial and eucaryotic membranes, this action israrely specific enough to permit these compounds to be usedsystemically. The only antibacterial antibiotics of clinical importancethat act by this mechanism are the polymyxins, producedby Bacillus polymyxa. Polymyxin is effective mainly againstGram-negativebacteria and is usually limited to topical usage. Polymyxins bind tomembrane phospholipids and thereby interfere with membrane function.Polymyxin is occasionally given for urinary tract infections caused by Pseudomonasstrains that are gentamicin, carbenicillin and tobramycin resistant.The balance between effectiveness and damage to the kidney and otherorgansis dangerously close, and the drug should only be given under closesupervision in the hospital.

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