Tetracyclines

how do ribosomal protection proteins confer resistance to tetracyclines?

RPP's (such as TetO or TetM) knock the tetracycline that has been bound to the Tet-1 site of the ribosome (cause dissociation of the tetracycline/ribosome complex) RPP's only act on the Tet-1 site, so free tetracycline can actually still bind to the Tet-2 site. this is not a mechanism of full resistance and is not a significant mechanism of bacterial resistance to tetracycline antibiotics

tetracyclines are a family of broad spectrum antibiotics produced by?

Streptomyces spp. Tetracyclines are effective against many organisms resistant to agents acting ont he cell wall

what drugs are included in the tetracycline class?

chlortetracycline tetracycline doxycycline minocycline tigecycline

tetracycline

hydrogenate the chlortetracycline and remove the Cl group to make it more stable in acidic conditions --> improve oral availability by a bit even though it is a bit more stable in acidic conditions compared to chlortetracycline, it's still not the best. the C6 hydroxyl group causes the compound to double bond in acidic conditions and become inactive high plasma concentration and long duration

tetracycline mechanism of action

inhibit protein synthesis by binding to the 16S rRNA of the 30S ribosomal subunit This blocks the aminoacyl-tRNA from binding to the ribosome --> prevents elongation of peptide chain. Requires Mg2+. tetraclyclines chelate the Mg2+, and then the Mg2+ in the complex now will chelate the mRNA Reversible and bacteriostatic

resistance to tigecycline

not a substrate for efflux pumps, so efflux pumps is NOT a mechanism of resistance to tigecycline active against bacteria that have the Tet(M) gene for ribsomal protection aka resistance to other tetracyclines (basically, tigecycline can overcome resistance due to efflux pumps and resistance due to ribosomal protection) resistance can develop quickly in some Gram(-) bacteria

chlortetracycline

this was the first tetracycline isolated and became the precursor for other members of the tetracycline class was widely used for years, but now is only used topically not stable in acidic conditions

tetracycline general structure

4 cyclic rings complex chemistry in aqueous solutions - amphoteric so tetracyclines can act as a base or an acid pKa1 = 2.8-3.4 C1 ketone to C3 enol pKa2 = 7.2-7.8 C10 phenol to C12 enol pKa3= 9.1-9.7 C4 dimethylamine compounds with a hydroxyl at the C6 can undergo acid or base promoted degradation C4 center can epimerize in weak acid to beta-diethylamine

tigecycline

minocycline derivative --> a t-butyl-glyclamido group to C9 this side chain is NOT stable, it is very easily cleaved off so this is only available as an injectable form. but the side chain makes it more active than earlier tetracyclines. the glycyl side chain increases binding to the rRNA and can form additional binding contacts with rRNA this was the first glycylcycline

tetracycline resistance

resistant strains are common against tetracyclines enzymatic inactivation -i.e. tetracycline destructase that destroys tetracyclines target modification -tetracyclines bind to the 16S rRNA of the 30S ribsomal subunit. Modify the 16S rRNA so tetracyclines can no longer bind energy dependent efflux mechanism -efflux mechanisms are a common resistance mechanism for many other ABX, not just tetracyclines -requires ATP -efflux pump actively transports the drug out of the cell before effective concentrations are reached and protein synthesis is halted -common, especially in Gram(-) bacteria ribosomal protection proteins -Tet(O) and Tet(M) are the most commone -found in various Gram(-) and Gram(+) bacteria -related to the elongation factors (GTPases) required in protein synthesis -->EF-Tu and EF-G

minocycline

semisynthetic dimethyalmine group added to the C7 of doxycycline structure like doxycycline, there is no hydroxyl at C6 so this compound is more stable in acidic conditions This has the longest half-life and is absorbed the best out of all the tetracyclines

doxycycline

semisynthetic compound --> remove the C6 hydroxyl compared to tetracycline so it is more stable in acidic conditions. (no OH group to protonate so no double bond) one of the most frequently prescribed tetracyclines active against malarial parasite Plasmodium falciparum. Can take this before going on trip to area where there are lots of mosquitos

why are tetracyclines contraindicated in children whose teeth are still growing and in pregnant women?

tetracycline can complex with Ca2+. This complex can be deposited in teeth and bone during gestation and early childhood. And indication of this is yellow teeth

tetracycline's selective toxicity results from?

tetracycline does not penetrate through mammalian cells very well, and it has low affinity for mammalian ribosome (recall: mammalian 50S 40S, bacterial 50S 30S) some bacteria will concentrate these drugs in the cell

how do tetracyclines enter Gram(-) cells?

tetracycline must coordinate with a di- or tri-valet metal ion (usually Mg2+) to enter the porin of the outer membrane in Gram(-) bacteria Once tetracycline is in the periplasmic space it must dissociate (Mg2+ is released in periplasmic space) to pass through cytoplasmic membrane Then it needs to get chelated again forit to bind to the ribosome and be active