Macrolides: Mechanisms of Action and Resistance

The macrolides are a group of drugs (typically antibiotics) whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Macrolides belong to the polyketide class of natural products.

Antibacterial

Macrolides are protein synthesis inhibitors. The mechanism of action of macrolides is inhibition of bacterial protein biosynthesis, and they are thought to do this by preventing peptidyltransferase from adding the peptidyl attached to tRNA to the next amino acid (similarly to chloramphenicol) as well as inhibiting ribosomal translocation. Another potential mechanism is premature dissociation of the peptidyl-tRNA from the ribosome.

Macrolide antibiotics do so by binding reversibly to the P site on the subunit 50S of the bacterial ribosome. This action is considered to be bacteriostatic. Macrolides tend to accumulate within leukocytes, and are, therefore, transported into the site of infection.

Diffuse panbronchiolitis

The macrolide antibiotics erythromycin, clarithromycin, and roxithromycin have proven to be an effective long-term treatment for the idiopathic, Asian-prevalent lung disease diffuse panbronchiolitis (DPB). The successful results of macrolides in DPB stems from controlling symptoms through immunomodulation (adjusting the immune response), with the added benefit of low-dose requirements.

With macrolide therapy in DPB, great reduction in bronchiolar inflammation and damage is achieved through suppression of not only neutrophil granulocyte proliferation but also lymphocyte activity and obstructive secretions in airways.[6] The antimicrobial and antibiotic effects of macrolides, however, are not believed to be involved in their beneficial effects toward treating DPB. This is evident, as the treatment dosage is much too low to fight infection, and in DPB cases with the occurrence of the macrolide-resistant bacterium Pseudomonas aeruginosa, macrolide therapy still produces substantial anti-inflammatory results

Resistance

The primary means of bacterial resistance to macrolides occurs by post-transcriptional methylation of the 23S bacterial ribosomal RNA. This acquired resistance can be either plasmid-mediated or chromosomal, i.e., through mutation, and results in cross-resistance to macrolides, lincosamides, and streptogramins (an MLS-resistant phenotype).

Two other types of acquired resistance rarely seen include the production of drug-inactivating enzymes (esterases or kinases), as well as the production of active ATP-dependent efflux proteins that transport the drug outside of the cell.

Azithromycin has been used to treat strep throat (Group A streptococcal (GAS) infection caused by Streptococcus pyogenes) in penicillin-sensitive patients, however macrolide-resistant strains of GAS are not uncommon. Cephalosporin is another option for these patients.

Bacterial Chromosome-Escalating Infectious Disease Threat

Many antibiotics, which we have taken for granted since the 1950's, are now becoming ineffective because bacteria have developed ways of acquiring resistance. The development of new antibiotics is lagging behind the loss of the old ones in this race to combat infectious disease. Simultaneously, there is an increase in infectious diseases around the world due to over population, globalization and urbanization. This results in a lethal combination of emerging diseases and loss of effective antibiotics. Multiple factors have contributed to this escalating scenario. The world is now a global village, there is a loss of control of national borders, there are significant populations of aging and immuno-compromised people, there are drastic chnges in global ecology, and migration pathways of animal and insect vectors are changing due to urbanization and global warming. Large networks of epidemiologists and scientists worldwide are now working to coordinate detection, diagnosis and treatment of infectious disease flare-ups in order to contain the threat of epidemics

Antimicrobial resistance

Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a horizontal fashion by conjugation, transduction, or transformation. Thus, a gene for antibiotic resistance that evolves via natural selection may be shared. Evolutionary stress such as exposure to antibiotics then selects for the antibiotic resistant trait. Many antibiotic resistance genes reside on plasmids, facilitating their transfer. If a bacterium carries several resistance genes, it is called multidrug resistant (MDR) or, informally, a superbug or super bacterium.

Meropenem Animation

Meropenem is an ultra-broad spectrum injectable antibiotic used to treat a wide variety of infections, including meningitis and pneumonia. It is a beta-lactam and belongs to the subgroup of carbapenem, similar to imipenem and ertapenem. Meropenem was originally developed by Sumitomo Pharmaceuticals. It is marketed outside Japan by AstraZeneca with the brand names Merrem and Meronem. Other brand names include Mepem (Taiwan) Meropen (Japan, Korea) and Neopenem (India) . It gained FDA approval in July 1996. It penetrates well into many tissues and body fluids including the cerebrospinal fluid, bile, heart valves, lung, and peritoneal fluid.

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Once Meropenam reaches Penicillin Binding Protein (PBPs) located at cytoplasm membrane it binds to them and interfere with their ability to create and modify peptidoglycan layer In PSEUDOMONAS AERUNGINOSA, Meropenam has a high affinity to the PBPII and PBPIII, this affinity is be lived to associate with high anti-pseudomonas activity has the result the cell wall weakens, osmotic pressure builds and cell ruptures and dies.

As a defense mechanism, bacteria develops resistance to antibiotics, the most common form of resistance to beta-lactam antibiotics is production of beta lactimases, enzymes that inactivate this antibiotics by breaking up the beta lactin rings.Merapenam retains high activity against PSEUDOMONAS AERUNGINOSA despite this organism inherent resistance to may drug classes. Studies have shown that Meropenam is not easily degrade by beta lactimases in the periplasmic space of Gram-negative Bacteria as other antibiotics. Merapenam has displayed significant stability to beta lactimases of most categories including penicillinases. Merapenam stability is believed to be link to 6alpha hydroxyl ethyl side chain on its chemical structure.

Plasmid Cloning animation

Process by which a plasmid is used to import recombinant DNA into a host cell for cloning.
Many diseases are caused by gene alterations. Our understanding of genetic diseases was greatly increased by information gained from DNA cloning. In DNA cloning, a DNA fragment that contains a gene of interest is inserted into a cloning vector or plasmid.

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The plasmid carrying genes for antibiotic resistance, and a DNA strand, which contains the gene of interest, are both cut with the same restriction endonuclease. The plasmid is opened up and the gene is freed from its parent DNA strand. They have complementary "sticky ends." The opened plasmid and the freed gene are mixed with DNA ligase, which reforms the two pieces as recombinant DNA.

This recombinant DNA stew is allowed to transform a bacterial culture, which is then exposed to antibiotics. All the cells except those which have been encoded by the plasmid DNA recombinant are killed, leaving a cell culture containing the desired recombinant DNA.

DNA cloning allows a copy of any specific part of a DNA (or RNA) sequence to be selected among many others and produced in an unlimited amount. This technique is the first stage of most of the genetic engineering experiments: production of DNA libraries, PCR, DNA sequencing, et al.