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Antibiotic resistance
and probiotics
P. Courvalin
The two types of resistanceThe 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 safetyProbiotics: 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 Tn916
Tn916
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 genesPotential 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
SusceptibleResistant
Transferability
Yes No
Acquired genes
Yes No
Insensitivity or mutation
No convincing evidence Convincing evidence
OKNot OK
Algorithm for decision making
Antibiotic resistance in Bacillus clausiiAntibiotic resistance in Bacillus clausii
Resistance to No of resistant strains
PenicillinsCephalosporinsAminoglycosides(kanamycin, tobramycin, amikacin)
MacrolidesTetracyclinesChloramphenicolRifampicin
44
SIN
4T4
NR
Susceptible to carbapenems, co-trimoxazole, fluoroquinolones, gentamicin, glycopeptides, oxazolidinones, streptogramins
Risk assessment of resistance disseminationRisk 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
The aadD2 genomic environment
aadD2 blaI blaR blaZ ytrA gntR
ABC Transporter
12323073
4322 3552 3477 3097 1176 181
Antibiotic resistance in Bacillus clausiiAntibiotic resistance in Bacillus clausii
Resistance to Mechanism Known gene Genetic basis Presence inref. 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
AcknowledgementsAcknowledgements
. Service de Microbiologie, CHU Côte de Nacre, CaenRoland Leclercq, Bülent Bozdogan, Sébastien Galopin
. Unité des Agents Antibactériens, Institut Pasteur, ParisGuy Gerbaud