The biological cost of mutational antibiotic resistance: any practical conclusions?

doi:10.1016/j.mib.2006.07.002

Current Opinion in Microbiology

Volume 9, Issue 5, October 2006, Pages 461-465

https://doi.org/10.1016/j.mib.2006.07.002 Get rights and content

A key parameter influencing the rate and trajectory of the evolution of antibiotic resistance is the fitness cost of resistance. Recent studies have demonstrated that antibiotic resistance, whether caused by target alteration or by other mechanisms, generally confers a reduction in fitness expressed as reduced growth, virulence or transmission. These findings imply that resistance might be reversible, provided antibiotic use is reduced. However, several processes act to stabilize resistance, including compensatory evolution where the fitness cost is ameliorated by additional mutation without loss of resistance, the rare occurrence of cost-free resistance mechanisms and genetic linkage or co-selection between the resistance markers and other selected markers. Conceivably we can use this knowledge to rationally choose and design targets and drugs where the costs of resistance are the highest, and where the likelihood of compensation is the lowest.

Introduction

There are several reasons to study how antibiotic resistance affects bacterial fitness. For example, the analysis of antibiotic resistance development has allowed, both in natural settings and in the laboratory, real-time studies of the effect of fitness and mutation parameters on the rate and trajectory of adaptive evolution in response to novel selection pressures. From a medical perspective, biological costs are important to determine, if we wish to predict resistance development and to evaluate interventions to reduce resistance. Several theoretical and experimental studies have shown that the cost of resistance is a main determinant of both the rate and extent of resistance development whilst under a given antibiotic pressure, and the rate by which resistance declines if antibiotic use is reduced [1, 2]. Thus, to evaluate the impact of interventions in order to reduce antibiotic resistance, quantitative models that include fitness parameters for the susceptible and resistant bacteria are required. At present, the actual values for these fitness parameters are in many cases unknown. Another motivation comes from drug development. Pharmaceutical companies generally judge the likelihood of resistance development against a new drug by focusing on the mutation rate to resistance, assuming that this rate is a major determinant of resistance development in clinical settings (e.g. see [3]). Even though mutation rates influence the rate of resistance development, the biological cost of resistance might be a more relevant predictor of the risk for resistance development. Thus, even though resistant mutants might form at a high rate, if the resistance severely reduces fitness, the frequency of resistant mutants might not rise in in the population [1, 2]. A rational antibiotic design strategy is therefore to identify targets for which the resistance mechanism has the most negative effect on fitness. In this review, which focuses on reports published from 2004–2006, the author discusses the difficulties with measuring and interpreting fitness costs, the impact of fitness on resistance development and some research areas where we need to increase our knowledge.

Section snippets

Difficulties with cost determinations and their interpretation

The fitness costs of antibiotic resistance are typically assessed by determining in isogenic strains if the resistance results in a reduced growth rate in vitro, in animals or in humans [1, 2, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19•, 20, 21•]. However, resistant bacteria isolated from clinical settings often have an undefined genetic basis for their antibiotic resistance and fitness and it is in this real world that the relevance of laboratory-based fitness cost measurements will

A bleak future for reversibility?

Even though it is widely believed that the costs found to be associated with many resistances might allow the more fit susceptible bacteria to out-compete the resistant ones when antibiotic pressure is reduced, this idea has only been tested in a few clinical studies with non-conclusive results [28, 29, 30]. Instead, the currently available data on the biological costs suggests that antibiotic resistance might be less easily reversed than previously anticipated, and the expected rate and extent

Relevant experimental measurements of costs

To assess the conditionality of the fitness effects, biological cost measurements need to be performed under as many conditions as possible and, in particular, under conditions similar to the clinical situation. Thus, competition, colonization and transmission studies in human volunteers are likely to give us the most relevant parameter values. Obviously such studies cannot be performed with many pathogens, but often they can be performed with non-pathogenic relatives or in animal models. An

Conclusions

The most important medical implication emerging from studies of the fitness costs of resistance is that the resistant clones are unlikely to disappear even if we reduce antibiotic use. Thus, reversibility studies at both the individual and community level indicate that often resistant bacteria are able to persist for a long time, even if no antibiotic selective pressure is present. Compensatory evolution, cost-free mutations and co-selection of resistance markers provide likely explanations for

Update

A recent study in M. tuberculosis shows that even though rifampin resistance is associated with a fitness cost, in antibiotic-treated patients resistant strains with no or low fitness reduction are often selected [48^•].

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

This work was supported by grants from the Swedish Research Council, the European Commission Frame Work Programs 5 and 6, Uppsala University and AFA Research Fund. The author thanks his co-workers for comments and support.

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View full text

The biological cost of mutational antibiotic resistance: any practical conclusions?

Introduction

Section snippets

Difficulties with cost determinations and their interpretation

A bleak future for reversibility?

Relevant experimental measurements of costs

Conclusions

Update

References and recommended reading

Acknowledgements

Curr Opin Microbiol

Curr Opin Microbiol

FEMS Immunol Med Microbiol

Platensimycin is a selective FabF inhibitor with potent antibiotic properties

Nature

Overexpression of the multidrug efflux pump SmeDEF impairs Stenotrophomonas maltophilia physiology

J Antimicrob Chemother

Fitness cost of SCCmec and methicillin resistance levels in Staphylococcus aureus

Antimicrob Agents Chemother

Rifampicin resistance and its fitness cost in Enterococcus faecium

J Antimicrob Chemother

Analysis of mupirocin resistance and fitness in Staphylococcus aureus by molecular genetic and structural modeling techniques

Antimicrob Agents Chemother

The isoleucyl-tRNA synthetase mutation V588F conferring mupirocin resistance in glycopeptide-intermediate Staphylococcus aureus is not associated with a significant fitness burden

J Antimicrob Chemother

Effect of rpoB mutations conferring rifampin resistance on fitness of Mycobacterium tuberculosis

Antimicrob Agents Chemother

Compensatory adaptation to the loss of biological fitness associated with acquisition of fusidic acid resistance in Staphylococcus aureus

Antimicrob Agents Chemother

Fitness cost due to mutations in the 16S rRNA associated with spectinomycin resistance in Chlamydia psittaci 6BC

Antimicrob Agents Chemother

Assessment of the fitness impacts on Escherichia coli of acquisition of antibiotic resistance genes encoded by different types of genetic element

J Antimicrob Chemother

Relative fitness of fluoroquinolone resistant Streptococcus pneumoniae

Emerg Infect Dis

Biological cost of single and multiple norfloxacin resistance mutations in Escherichia coli implicated in urinary tract infections

Antimicrob Agents Chemother

Reduction of the fitness burden of quinolone resistance in Pseudomonas aeruginosa

J Antimicrob Chemother

Overexpression of the multidrug efflux pumps MexCD-OprJ and MexEF-OprN is associated with a reduction of type III secretion in Pseudomonas aeruginosa

J Bacteriol

23S rRNA base pair 2057–2611 determines determines ketolide susceptibility and fitness cost of the macrolide resistance mutation2058A → G

Proc Natl Acad Sci USA

Novel mechanism of resistance to oxazolidinones, macrolides, and chloramphenicol in ribosomal protein L4 of the pneumococcus

Antimicrob Agents Chemother

Reducing the fitness cost of antibiotic resistance by amplification of initiator tRNA genes

Proc Natl Acad Sci USA

Mutation frequency and biological cost of antibiotic resistance in Helicobacter pylori

Proc Natl Acad Sci USA

Growth competition of macrolide resistant and susceptible Helicobacter pylori strains

Microbiol Immunol

Analysis of rpoB and pncA mutations in the published literature: an insight into the role of oxidative stress in Mycobacterium tuberculosis evolution?

J Antimicrob Chemother