Antibiotic Resistance
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Antibiotic Resistance

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    Antibiotic Resistance Antibiotic Resistance Presentation Transcript

    • Antibiotic resistance and probiotics P. Courvalin
    • The two types of resistance . Intrinsic or natural (insensitivity): - present in all the strains of the genus/species - not transferable - defines the spectrum of activity of an antibiotic . Acquired: - exogenous gene - mutation
    • Probiotics: Antibiotic multiresistance and safety . Pros: - co-administration with antibiotics . Cons: - transfer of resistance to human bacterial pathogens . directly . indirectly via the commensal flora - acquisition of resistance from human commensals - shortage of antibiotics in case of infection
    • Resistance mechanisms
    • Bacterial genome
    •  
    • Plasmid transfer by conjugation
    • Intra- and Inter-cellular mobility of Tn 916 Tn 916 plasmid chromosome Integration (Int) Excision (Int + Xis) Integration (Int) Donor Recipient Transfer (Tra)
    •  
    • Combinatorial genetics of antibiotic resistance Vector Bacteria Plasmids Transposons Host Mammals Bacteria Replicons
    • Potential for spread of resistance genes . High: - gene carried by a mobile genetic element (self-transferable plasmid or transposon) . Low: - chromosomal gene(s) responsible for insensitivity - present in all the strains of the genus/species - absence of in vitro / in vivo transfer - absence of known acquired genes - genus/species specific gene - co-localisation with chromosomal genes - flanking sequences: . house-keeping genes . no mobile genetic element
    • Phenotype Susceptible Resistant Transferability Yes No Acquired genes Yes No Insensitivity or mutation No convincing evidence Convincing evidence OK Not OK Algorithm for decision making
    • Antibiotic resistance in Bacillus clausii Resistance to No of resistant strains Penicillins Cephalosporins Aminoglycosides (kanamycin, tobramycin, amikacin) Macrolides Tetracyclines Chloramphenicol Rifampicin 4 4 SIN 4 T 4 NR Susceptible to carbapenems, co-trimoxazole, fluoroquinolones, gentamicin, glycopeptides, oxazolidinones, streptogramins
    • Risk assessment of resistance dissemination . Identification of the resistance genes - cloning and deduced sequence comparison . Characterisation of the biochemical mechanisms . Elucidation of the genetic basis - co-localisation with a chromosomal gene - sequence analysis of the flanking DNA . Attempts of in vitro resistance transfer to: - Enterococcus faecalis and Enterococcus faecium - Bacillus subtilis
    • Sequence comparison of aminoglycoside 4’- O -nucleotidyltransferases
    • Localisation of aadD2 in Bacillus clausii Driver NR SIN T Ref. OC NR SIN T Ref. OC Probe rrs aadD2
    • Sequence comparison of aadD2 promoters in B. clausii S I N A A C AG C T A TG A CA T G A TT A C G AA T T C AA G C G TG C G A AA T C G TC A C T AC C T G AA A C A AA T G D S M 8 71 6 A A C AG C T A TG A CA T G A TT A C G AA T T C AA G C G TG C G A AA T C G TC A C T AC C T G AA A C A AA T G * * * ** * * * ** * ** * * * ** * * * ** * * * ** * * * ** * * * ** * * * ** * * * ** * * * ** * * * ** * * - 3 5 - 1 0 -3 5 S I N G C A AA C A A TT A TA T C A TT T T C C T T G A C A A T G A AA T G C CT T T T T G G T A A C C TT T T C TT A A T - 3 5 - 1 0 D S M 8 71 6 G C A A AC A A T TA T G T CA T T T TC C T T G C C A A T G A AA T G C CT T T T A G G T A A C C TT T T C TT A A T * * * ** * * * ** * * * * * ** * * * ** * * ** * * * ** * * * ** * * * * * * * ** * * * ** * * * ** * * - 1 0 S I N C A A A C A TA T A G G GG T G G TT C A A GT G C A CC G A A AA A AA G T C CC C C G TT A A T CT C G A GG T C C D S M 8 71 6 C A A AC A T A TA G GG G T G GT T C A AG T G C AC C G A AA A A A AG T C C CC C G T TA A T C TC G A G GT C C * * * ** * * * ** * ** * * * ** * * * ** * * * ** * * * ** * * * ** * * * ** * * * ** * * * ** * * * ** * * R B S S I N T C C AT T C A TC G TT C A T GT C A C AC A C T CA A A T TG A A A C A A A AG G A G A T G G A AG T G A A T G D S M 8 71 6 T C C AT T C A TC G TT C A T GT C A C AC A C T CA A A T TG A A A C A A A AG G A G A T G G A AG T G A A T G
    • The aadD2 genomic environment aadD2 blaI blaR blaZ ytrA gntR ABC Transporter 1232 3073 4322 3552 3477 3097 1176 181
    • Antibiotic resistance in Bacillus clausii Resistance to Mechanism Known gene Genetic basis Presence in ref. strains Penicillins Inactivation No Chromosome + Cephalosporins Inactivation No Chromosome + Aminoglycosides Inactivation No Chromosome + (kanamycin, tobramycin, amikacin) Macrolides Target modification No Chromosome + Tetracyclines ? ? ? - Chloramphenicol Inactivation No Chromosome - Rifampicin Target modification Mutation Chromosome - R genes - not located on a plasmid (Tc?) - not transferable in vitro
    • Acknowledgements . Service de Microbiologie, CHU Côte de Nacre, Caen Roland Leclercq, Bülent Bozdogan, Sébastien Galopin . Unité des Agents Antibactériens, Institut Pasteur, Paris Guy Gerbaud