~Gram –ve chloramphinicol acetyl transferase against chloramphinicol . b)Microorganism alters its permeability to the drug eg tetracyclin and polymyxin . Streptococci have natural barrier to aminoglycosides . acer:
c)Microorganism develops an altered structural target eg:chromosomal resistance to aminoglycosides “30s ribosomal subunit’’ Erythromycin resistant organisms altere receptors in 50s ribosomal subunit. Penicillin resistance change in penicillin binding protein “PBP”.
d)Microorganisms develop an altered metabolic pathways that bypass the reaction inhibited by the drug eg:
Sulfonamides can use the preformed folic acid without need to extracellular PABA.
e)Microorganisms alter an enzyme eg:
Trimethprim resistant bacteria dihydrofolic acid reductease is inhibited .
Origins of the drug resistance ORIGINS Non genetic Genetic chromosomal Extrachromosomal
*Active replication of bacteria is required for most antibacterial drug action eg :
Mycobacterim tuberclosis stay many years in the body with slow multiplying.
* Microorganism may lose target structure and so becomes resistant ,eg: penicillin susceptible organisms may have difficiency in L-aminoacids cell wall diff- and so become resistant to cell wall
1 Non genetic origin:
Inhibitor drugs (penicillin + cephalosporins).
*microorganisms may infect cells which drug cann ’ t reach them,eg:
Aminoglycosides salmonella enteric fever
Because salmonellae are intracellular microorganisms and aminoglycosides cannt enter the cell.
Either :a)chromosomal “mutation” :this develops as a result of spontaneous mutation in a locus that controles susceptibility to a given drug
* Chromosomal mutants are most commonly resistant by virtue of changes in a structural receptor of drug ,eg mutation in the gene controlling the structural protein “of streptomycin
2 Genetic origin :
Receptor ) result in streptomycin resistance .
b)extrachromosomal “plasmid mediated resistance”: bacteria often contain extrachromosomal gentic elements called plasmids .
*R-factor are a class of plasmids , circular ,double stranded DNA that carry genes for resistance to one –and often several – antimicrobial drug and heavy metals “Co ,Hg”.
*R-factor composed of two parts :
1 resistant – transfer factor “RTF” segment of plasmid that responsible for intracellular transfer .and
2 R-determinant : that carries the resistance genes .
~Dissemintion by bacterial conjugation mainly.
Clinical importance of extrachromosomal resistance :
1) It occurs in many different species , specially gram –ve rods .
2) Plasmids frequentely mediate resistance to multiple drugs .
3)plasmids have a high rate of transfer from one cell to another by conjugation.
The mechanisms of resistance :
The plasmid genes control the formation of enzs capable to destory the drugs eg:plasmids determine resistance to penicillins and cephalosporins by carring genes for the fomation B-lactamase
~Genetic material and plasmid can be transferred by transformation ,transduction ,conjugation and transposition.
Is the up take of the extra cellular DNA by bacteria thus ,altering its genotype .
This can occur through labrotary manipulation (e.g: in recombinant DNA technology ).
a) DNA must bind to the cell surface.
b) The bound DNA taken up through the cell membrane .
c)the DNA fragment is integrated into the host chromosome or replicates as plasmid.
The genetic transfer occur when a fragment of DNA is carried to the recipient cell by virus “bacteriophage “ e.g :the plasmid carring of the gene for B-lactamase production ,can be transferred from apenicillin –resistant to a susceptible staph aureus .
Conjugation (plasmid- mediated transfer):
It is a unilateral transfer of genetic material between bacteria of the same or different genera occurs during amating (conjugation ) process.
This is mediated by afertility factor that result in extension or extrusion of sex pili from the doner (F+) cell to the recipient (F-).
A transfer of short DNA sequences (transposons,transposable element ) occurs between one plasmid and another or between a plasmid and a portion of the bacterial chromosome .
cross resistance :
Microorganisms resistant to a certain drugs may also be resistant to other drugs that share a mechanism of action eg:
~different aminoglycosides are closely related chemically
~macrolides and lincomycins :have a similar mode of action or binding .
Limitation of drug resistance :
1 by maintainig sufficiently high level of the drug in the tissues to inhibit both the original population and the first step mutants
2y simultaneously administering two drugs that don’t give cross resistance (each of which delays the emergence of mutants resistant to the other drug eg :Rifampin and isoniazide in treatment of T.B)
3 by avoiding exposture of microorganism to a particularely valuable drug by limittig its use specially in hospital .
4health awareness about missuse of antibiotics
Specific mechanisms of resistance
*penicillins and cephalosporins :
1cleavage by B-lactamases
2due to change in the PBP
esistance of N.gonorrhoea to penicillin is due to poor permeability to the drug.
4 olerance (decrease of growth but not killing of bacteria)
*Vancomycin :the resistance is caused by a change in the peptide component of peptidoglycan from D-alanine:D-alanine (normally),to D-alanine :D-lactate (abnormal; no drug bindig )
* Aminoglycosides :three mechanisms :
1 modification of the drug by plasmid – encoded phosphorylating , adenylating and acetylating enzymes .
3Decrease permeability of the bacteria to the drug
( hospitals should be the Mecca of all types of Staphylococcus)
staphylococcus is one of the most resistant organisms to antimicrobial drugs .