Macrolides, Clindamycin & Ketolides Polymyxins

Sungkyunkwan University School of Medicine

Macrolides, Clindamycin & KetolidesMacrolides, Clindamycin & KetolidesPolymyxinsPolymyxins

Kwan Soo Ko


Macrolides- Erythromycin- Azithromycin- Clarithromycin

Unrelated chemicallyBut, many similar biological properties

Lincosamides- Lincomycin - Clindamycin


Ketolides- derivative of erythromycin- Telithromycin


Macrolides

14-membered 15-membered

Erythromycin Clarithromycin Azithromycin


Erythromycin- in 1952- from a strain of Saccharopolyspora erythra

(Streptomyces erythreus) (soil from the Philippines)

- Active component, erythromycin A

14-member macrocyclic lactone ring,attached to two sugar moieties


Erythromycin

Inhibits RNA-dependent protein synthesis at the step of chain elongation

Several functional groups binds to sequenceson domain V of 23S rRNA

(a component of 50S subunit of ribosome)


Binding site near peptidyltrasnferase center

Prevention of peptide chain elongation by blocking of polypeptide exit tunnel

Dissociation of peptidyl-tRNA from ribosome


Studies of E. coli and S. aureus

Erythromycin also inhibits formation of 50S ribosomal subunit


Erythromycin resistance

Decreased microbial entry or increased export of drug

Target site alterations

Drug inactivation


Cytoplasm

Ribosomes5030

5030

5030

Target site alterationby erm

Macrolide

Efflux by mef

Weisblum B. In: Gram-Positive Pathogens. 2000:694-710.Hyde TB et al. JAMA. 2001;286:1857-1862.


Intrinsic decreased permeabilityof outer membrane to macrolides

- Enterobacteriaceae- Pseudomonas spp.- Acinetobacter spp.

- Cell-free systems and protoplasts of organisms are susceptible to macrolides


Chromosomally encoded efflux pumps

- By proton active force or by hydrolysis of ATP- in S. epidermidis and S. aureus,

plasmid-mediated erythromycin resistance (MLSBphenotype) by active efflux encoded by msrA gene

- in S. pyogenes, S. pneumoniae & enterococci,M phenotype (14- and 15-member macrolides, but not 16-member macrolides, lincosamides, and streptogramin B): encoded by mefA gene

- Low-level resistance


Target site alterations

- Mutations in genes for 50S ribosomal proteins or bases or critical domains of the 23S rRNA receptor site

- Be associated with a decreased binding affinity - High-level resistance- In some strains of S. pneumoniae, H. pylori, M. avium,

B. subtilis, S. pyogenes, Campylobacter spp., M. pneumoniae, E. coli & S. aureus


Alterations in the 23S rRNA of the 50S ribosomal subunitby dimethylation of adenine at a defined position(A2058 residue of domain V)

- be associated with resistance to erythromycin and most other macrolides (M), and sometimes to the lincosamides (lincomycin & clindamycin)(L), and streptogramin B (SB)→ MLSB phenotype

- be mediated by the erm(erythromycin ribosome methylation)


Drug inactivation

- By phosphotransferasesIn strains of S. aureus, E. coli & Nocardia spp.mphA, mphB & mphC

- By esterase genes (ereA & ereB) on plasmidsHydrolysis of macrocyclic lactone of erythromycinIn strains of E. coli, Klebsiella spp., Citrobacter spp., Proteus spp. & Enterobacter spp.


Azithromycin & Clarithromycin

To improve the qualities of erythromycin- better oral absorption, a longer half-life, fewer

gastrointestinal side effect & a greater antimicrobial spectrum of activity


Erythromycin

Azithromycin

methyl-substituted nitrogen

Clarithromycin

methoxy group

→ increase of stability in gastric acid, improving absorption by oral route


Azithromycin, clarithromycin & erythromycin- bind to the same receptor on 50S ribosomal subunit

& inhibit RNA-dependent protein synthesis by the same mechanism

Azithromycin (15-member macrolides)- greater activity than the 14-member macrolides

against gram-negative bacteria (especially for M. catarrhalis and H. influenzae)due to better penetration the outer envelope

Resistance mechanisms to azithromycin & clarithromycin

- the same as or similar to those for erythromycin


Ketolides

New class of semisynthetic agents derived from erythromycin

Increased acid stabilityIncreased antibacterial potency against many bacteria

resistant to macrolidesUnability to induce the MLSB phenotype


Telithromycin

Be approved for clinical usein the US in April 2004in Europe in 2001

Serious and fatal hepatotoxicity in 2006


Action mechanism essentially similar to that of erythromycin

By interacting closely to peptidyl transferase site of 50S ribosomal subunit

& by interfering with the formation of 50S ribosomal subunit


Different nature of their interaction with the ribosome between telithromycin and erythromycin

Higher binding affinity of telithromycindue to the dual interaction with domains V and II of 23S rRNA

Direct interference with elongation polypeptide chain+

Inhibition of formation of the 50S ribosomal subunitInhibition of the 30S ribosomal subunit (at higher conc.)


Uncommon resistance to telithromycin

- Poor inducer or poor substrate for bacterial strains expressing efflux mechanisms of resistance

- Poor inducer of the MLSB methylase genes; potent against S. pneumoniae isoaltes with the consitutive erm gene

Rare bacterial strains with increased MICs to telithromycin- by mutations in the bases of 23S rRNA of the 50S

ribosomal subunit or in ribosomal proteins- most, laboratory isolates


Lincomycin

In 1962, From Streptomyces lincolnensis(soil near Lincoln, Nebraska)

Biological properties similar to those of erythromycin, but chemically unrelated(an amino acid linked to an amino sugar)

Chemical modification

Clindamycin


Clindamycin

Increased antibacterial potency & absorption after oral administration


The same or overlapping 50S ribosomal binding sites - as those for macrolides and chloramphenicol

Inhibition of protein synthesis in early chain elongationby interference with the transpeptidation reaction, possibly through blockade of the P site

Also stimulate the dissocation of peptidyl-tRNA from ribosomes (like macrolides)


Resistance mechanisms

Alteration in the 23S rRNA of 50S ribosomal subunitby methylation of adenine (as in macrolides)

- usually plasmid-mediated - MLSB type of resistance

- In S. aureus, macrolide-inducible varietyby positive erythromycin-clindamycin “D-test”


Exposure to clindamycin in vitro or in vivo may result in clindamycin resistance due to selection of preexisting constitutive erm mutants, especially if the organism is at high innoculum



Mutations in the bacterial rRNA - in some strains of Mycobacterium smegmatis

Alteration in particular 50S ribosomal proteins of the receptor site (as in macrolides)



Inactivation of lincomycin and clindamycin- by a few isolates staphylococci and Bacteroides spp.- plasmid-mediated 3-lincomycin 4-clindamycin 0-

nucleotidyltransferase- catalyze the nucleotidylation of the hydroxyl group in

position 4 of clindamycin

Enterobacteriaceae, Pseudomonas & Acinetobacter- intrisically resistance to clindamycin- due to poor permeability of the cellular outer envelop


Polymyxins

Polymyxin B & polymyxin E (colistin)

Old drug, discovered in 1947 (Bacillus polymyxa)Colistin became available for clinical use in the 1960s

but has been abandoned sine 1970s because of neurotoxicity and nephrotoxicity

Re-introduction because of remarkable increase in resistance to antimicrobial agents currently available

- Polymyxins are sometimes the only available active antibiotics


Colistin (polymyxin E)

Polymyxin B



Action mechanism of colistin

Polycationic and with both hydrophilic and lipophilic moieties

- bactericidal drug binding to LPS and phospholipids in the outer cell membrane of gram-negative bacteria

- competitively displaces divalent cations from the phosphate groups of membrane lipids, leading to disruption of the outer cell membrane, leakage of intracellular contents, and bacterial death

Colistin can bind and neutralize LPS and prevent the pathophysiologic effects of endotoxin


Colistin Resistance

AntibioticsMIC (mg/L)

% S / R50% 90% Range

Polymyxin B ≤1 2 ≤1 - >8 97.9 / 2.1

Ceftazidime 16 >16 ≤1 - >16 44.6 / 48.3

Cefepime 16 >16 ≤0.12 - >16 47.7 / 37.3

Ampicillin/sulbactam 8 >32 ≤0.25 - >32 56.2 / 31.6

Imipenem 0.5 >8 ≤0.06 - >8 81.1 / 15.8

Meropenem 1 >8 0.016 - >8 77.7 / 17.0

Ciprofloxacin >2 >2 ≤0.016 - >2 44.3 / 55.0

Amikacin 4 >32 ≤0.25 - >32 60.2 / 35.8

SENTRY Data 2001-2004 (Gales et al., 2006)



Li et al. AAC 50:2946 (2006)Tan et al. AAC 51:3413 (2007)

Extensive emergence of colistin-resistant A. baumannii subpopulations provoked by exposure to colistin


Colistin resistance

Specific modification of the lipid A component of the outer membrane lipopolysaccharide, resulting in a reduction of the net negative charge of the outer membrane

Proteolytic cleavage of the drug

Activation of a broad-spectrum efflux pump

Two-component signaling systems PmrAB and PhoPQ- be involved in sensing environmental pH, Fe3+, and Mg2+

levels, leading to altered expression of a set of genes involved in lipid A modification


Mutational analysis of the pmr operon

Adams et al. AAC (2009)

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Macrolides, Clindamycin & Ketolides Polymyxins

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