ReviewThe biological cost of antibiotic resistance
Introduction
The use of antibiotics by humans can be seen as an evolutionary experiment of enormous magnitude, a window from which to view not-quite-natural selection operating in real time. Within 50 years, the number of species and strains of pathogenic and commensal bacteria resistant to antibiotics and the number of antibiotics to which they are resistant has increased virtually monotonically world-wide. Infections that had been readily treatable by chemotherapy may no longer be 1, 2, 3, 4. It is clear that the evolution and spread of resistance can be attributed to the use and overuse of antibiotics (also see Guillemot’s review on antibiotic usage, this issue, pp 494–498). Not so clear is whether this situation can be reversed in a reasonable amount of time. That depends on factors which we may be able to control, such as the rate and pattern of antibiotic use, but also on factors over which we have no control, the biological cost resistance imposes on the fitness of bacteria 5•, 6•, and the rate and degree to which natural selection will ameliorate these costs.
Section snippets
Measuring the biological costs of resistance
The fitness of the pathogens that are the targets of antibiotic therapy is a complex character with a number of interrelated elements. The most important of these are the relative rates at which antibiotic-sensitive and -resistant bacteria firstly, reproduce and die (compete) in infected hosts and the environment, secondly, are transmitted between hosts, and thirdly, are cleared from infected hosts 5•, 6•. At any given time, the magnitude of these elements will depend on the extent and pattern
Experimentally estimating the costs of resistance and studying the adaptation to those costs
Experimental studies of the biological cost of resistance have focused almost exclusively on the relative rates of growth, survival and competitive performance of antibiotic-sensitive and -resistant bacteria. In some studies, the costs of resistance were estimated from the exponential growth rates of sensitive and resistant bacteria in monocultures 7••, 8• but more commonly they have been measured by pairwise competition experiments. Mixtures of otherwise isogenic sensitive and resistant
Is there a cost to resistance?
It is convenient to separately consider the costs of resistance encoded by chromosomal mutations, where resistance is achieved primarily by the modification of target molecules 17, 18, 19, 20, 21, and that determined by accessory elements, where resistance is generally due to enzymes that inactivate the antibiotic or pumps that remove it from the cell 17, 18, 19, 20, 21, 22, 23. Resistance encoded by accessory elements may also give rise to costs associated with the replication and maintenance
Reversion, compensatory evolution and amelioration of fitness costs
Although occasionally, in the absence of antibiotics, drug-sensitive revertants have evolved in most cases, adaptation to the costs of chromosomal resistance in vitro and in vivo has been through compensatory mutations (Table 2). In the majority, but not all cases, the second site mutations compensating for the cost of resistance have been identified. These occur by additional (or alternative) mutations at the same locus as the resistance gene, intragenic suppression, or at other loci,
Reality
Experimental studies of the costs of resistance, and adaptation to those costs make a number of predictions that can be tested (and rejected) by examining the resistance genes and accessory elements found in bacteria isolated from humans and domestic animals to see if the same mutations ascend. The results of the few tests of this type done to date suggest that chromosomal mutations responsible for acquired resistance in pathogenic bacteria are likely to be the same as those mutations observed
Implications
Although it has been long thought that antibiotic-resistance genes and accessory elements would engender a cost in the fitness of bacteria, the actual evidence for this being the case is, at best, modest and that which has been gathered recently does not paint a rosy picture for the future of the resistance problem. Resistance mutations, such as those found in the bacteria from patients treated with antibiotics, have virtually no cost when measured by competition experiments in vitro or in
Acknowledgements
This endeavor was supported by the Swedish Natural Sciences and Medical Research Councils, Swedish Institute for Infectious Disease Control, Lovens Pharmaceutical Products (DI Andersson), the US National Institutes of Health, GM3372 and AI40662, and the Swedish National Science Foundation — NFR, (BR Levin). We wish to thank Anders Håkansson for reading this manuscript and useful comments and suggestions.
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
References (37)
Epidemiology of emerging/re-emerging antimicrobial-resistant pathogens
Curr Opin Microbiol
(1998)Quantifying fitness and gene stability in microorganisms
Biotechnology
(1991)Overview of mechanisms of bacterial resistance
Diagn Microbiol Infect Dis
(1989)- et al.
Expression of tetracycline resistance in pBR322 derivatives reduces the reproductive fitness of plasmid-containing Escherichia coli
Gene
(1985) - et al.
Tuberculosis — commentary on a reemergent killer
Science
(1992) Epidemiology of drug resistance: implications for a post-antimicrobial era
Science
(1992)The Antibiotic Paradox: How Miracle Drugs are Destroying the Miracle
(1992)- et al.
The population genetics of antibiotic resistance
Clin Inf Dis
(1997) - et al.
The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistance
Proc Natl Acad Sci USA
(1999) - et al.
Virulence of antibiotic resistant Salmonella typhimuirium
Proc Natl Acad Sci USA
(1998)
Novel ribosomal mutations affecting translational accuracy, antibiotic resistance and virulence of Salmonella typhimurium
Mol Microbiol
Evolution of a bacteria/plasmid association
Nature
Coevolution in bacteria-plasmid populations
Evolution
Adaptation to the fitness cost of antibiotic resistance in Escherichia coli
Proc R Soc London
Selection in chemostats
Microbiol Rev
Genetic analysis of a plasmid-encoded, host genotype-specific enhancement of bacterial fitness
J Bacteriol
Plasmid macro-evolution: selection of deletions during adaptation in a nutrient-limited environment
Genetica
Cited by (648)
Unveiling a novel mechanism for competitive advantage of ciprofloxacin-resistant bacteria in the environment through bacterial membrane vesicles
2024, Journal of Hazardous MaterialsDesign, synthesis, molecular docking and antimicrobial activities of novel triazole‐ferulic acid ester hybrid carbohydrates
2022, Journal of Molecular StructureBacteria can compensate the fitness costs of amplified resistance genes via a bypass mechanism
2024, Nature CommunicationsIn vitro susceptibility of nontuberculous mycobacteria in China
2024, BMC Infectious Diseases