Antimicrobial resistance: biologyAntimicrobial resistance: biology and evolution
Stephen H. GillespieStephen H. GillespieUniversity of St Andrews
OverviewOverview
• Introduction, definitions and scope• Acquisition of resistanceAcquisition of resistance• Adaptation to resistance• Transmission among bacteria• Transmission in the communityTransmission in the community• Conclusions
Anti microbial resistance: definitionAnti‐microbial resistance: definition
Natural resistance Organisms lack the target of the antimicrobial or the antimicrobial is unable toantimicrobial is unable to penetrate cellular structures
Acquired resistance Previously susceptibleAcquired resistance Previously susceptible organism that has acquired new mechanisms to overcome the effect of the anti‐microbial
Acquisition
Adaptation
Transmission(bacterial)
Transmission(human/animal)
Emergence of anti‐microbial resistance overview
Nat Rev Microbiol 2010, 8
Acquisition of anti microbial resistanceAcquisition of anti‐microbial resistance
l f i i i h iExamples of acquisition mechanisms
Chromosomal mutation gene level change
Gene inactivation/deletion gene level changeGene inactivation/deletion gene level change
Gene mosaicism gene level change
Plasmid gene acquisition
Integron gene acquisition
Phage gene acquisition
Emergence of resistance: a dynamic balance
Fitness costAntibiotic effect
Growth rate
Resistance levelrate (MIC)
For M. tuberculosis/rifampicinresistance clinical frequencyi l d h i fiis related to the primary fitnesscost
What is defined as a “fit” mutantdepends on context
Mariam et al., AAC 2004; 48:1289‐1294
Jenkins et al., JAC 2009; 63: 1118‐1120Context changes selection and “fitness”
Ancestral Beijing Modern BeijingClinical isolates
Bergval. personal communication
Mutation at sub‐therapeuticconcentrations
I t l f l ti d fitInterplay of selection and fitnessvaries by different antibiotic
Gillespie et al., JAC 2005; 56:344‐8
An obvious evolutionary progressionAn obvious evolutionary progression
The selective pressures mayp ychange
Acquisition
Adaptation
Transmission(bacterial)
Transmission(human/animal)
Emergence of anti‐microbial resistance overview
pHe96 backgroundpHe96 background
pBR322 background
Acquisition
Adaptation
Transmission(bacterial)
Transmission(human/animal)
Emergence of anti‐microbial resistance overview
Transfer of antibioticTransfer of antibiotic resistance between species and by a spec es a d by avariety of mobile genetic elements
Acquisition
Adaptation
Transmission(bacterial)
Transmission(human/animal)
Emergence of anti‐microbial resistance overview
For M. tuberculosis/rifampicinresistance clinical frequencyi l d h i fiis related to the primary fitnesscost
Lineage No.
Number of isolates
% (number) resistant
Resistance profile(s) Relative Rate of Transmissionisolates resistant Transmission (RRT)
15 16 87.5% (14) 10 x INH mono-resistance1 x INH and eth resistance
0.141 x INH and eth resistance1 x INH, RIF, clari & eth resistance2 x streptomycin mono-resistance
19 15 6.7% (1) U = 3
INH mono-resistance 11
41 21 9.5% (2) U = 2
INH mono-resistanceRIF & INH resistance
8.50
43 10 0% (0) N/A N/A43 10 0% (0) N/A N/A
54 13 0.8% (1)U = 1
INH mono-resistance 11
61 13 0.8% (1)U = 1
INH mono-resistance 12
07:118 (0 82) 04:503 (0.94)07 116 (1 09)07:118 (0.82)
katG S315T( )
inhA C→T -767 07:116 (1.09)inhA C→T -767ethi ®
04:018 (0.78)
02:302 (1.07)
03:303 (0.89)04:493 (1.01)Both: inhA C→T -767 02:292
04:018 (0.78)inhA C→T -767R, clari, ethi ®
02:302 (1.07)S mono-®02:113 (1.01)fully sens
767 02:29203:039 (0.92)04:211 (0.96)All: inhA C→T -767
04:194 (0.93)katG S315T
05:046 (1.01)fully sens
03:313 (1.08)S mono-®
Resistance, fitness and a tuberculosis outbreak
Antibiotic resistantgene flowgene flow
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ConclusionsConclusions
• There is no such thing as “resistance”• Each antibiotic‐bacterial pairing is a separate p g pbiological system
• These systems are not independent but interact• These systems are not independent but interact with each other based on biological epizoologicald id i l i l i i land epidemiological principles
• Promiscuous antibiotic drug use is an important driver tipping the balance in favour of increased density of antibiotic resistance genes y g
AcknowledgementsAcknowledgements
• EU FP7 PAR Contract no 241476
• Katarina Oravcova• Taciana Kasciukovic
• European Developing Country Clinical Trials
• Holly Owen• Rob Shorten (UCL)
Partnership• MRC
• Rob Shorten (UCL)• Tim McHugh (UCL)• Lasantha Ratnayake(Dundee)