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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Jonathan Swift “On Poetry”

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)