Normal Protein

Mutations can improve normal protein function resulting in increased fitness relative to the environment. Many mutations work by generating more effective enzymes or through novel catalytic mechanisms. Explore Evolution is wrong to claim that mutations must impair a protein's normal functioning and impose a fitness cost. Explore Evolution does not even discuss mutations in cis-regulatory elements (CREs), which have minimal fitness costs and are considered by many evolutionary biologists to have the greatest potential for generating evolutionary change (Prud'homme et al., 2007). Explore Evolution also misrepresents the basic notion of fitness, by failing to note that fitness depends on the environment.

After saying that a "resistance gene" does not develop through mutation, Explore Evolution then says mutations do confer resistance but with a "fitness cost."

[A] mutation [changes] the shape of the active site on the "target" protein so that the antibiotic no longer recognizes the site. However, that very same mutation also impairs that strain's ability to perform other vital functions like information processing. Microbiologists refer to this as the "fitness cost" of a mutation.
Explore Evolution, p. 103
Experiments show that once antibiotics are removed from the environment, the original (non-resistant) strain "out-competes" the resistant strain, which dies off within a few generations.
Explore Evolution, p. 103

Explore Evolution significantly misrepresents how antibiotic resistance arises in this description. For example, methicillin resistance is due to generation of a new binding site for penicillin-like drugs on a protein that previously did not have this activity (Wu et al., 1996, 2001). Vancomycin resistance is due to the generation of a novel enzyme that bypasses the vancomycin-susceptible step. Resistance to extended-spectrum antibiotics is due to the evolution of beta-lactamases with increased catalytic efficiency (Sideraki et al., 2001).

Increased fitness cost is not necessarily related to enzyme "impairment." Consider the example of the methicillin resistance gene. It produces a new protein which binds methicillin, preventing methicillin from acting. However, producing this protein costs energy and resources. In the absence of methicillin, making the protein diverts resources way from growth, and so the methicillin resistant bacteria will grow more slowly than a methicillin sensitive bacteria in the absence of the antibiotic. This slower growth decreases fitness.

One of the best studied examples of antibiotic resistance is the case of resistance to the antibiotic streptomycin. Streptomycin kills bacteria by interfering with protein assembly on the ribosome, turning out garbage proteins, by binding to the S12 subunit of the 30S ribosomal particle in bacteria. The 30S ribosomal particle is a multi-subunit structure which in turn forms part of the protein synthesizing ribosomal particle. The S12 subunit together with 16S RNA forms part of the proof reading centre of the transfer RNA (tRNA) acceptor binding site. A mutation that results in the substitution of threonine or asparagine for lysine at position 42 in the rspL gene results in streptomycin failing to bind to S12, with resulting resistance of the bacteria to the antibiotic streptomycin. This mutant version is actually more accurate, i.e. more specific, than the wild type. The wild-type proof reading center makes a few mistakes even in the absence of streptomycin, and the mutant forms make even fewer mistakes than the wild type, roughly 85% fewer (Bjorkman et al., 1999). This is a classic example of a beneficial mutation. Furthermore it was work on this mutation that determined that mutations were random.

Thus we can see that the mutation that produces streptomycin resistance doesn't impair information processing, it makes it more accurate. However, this increased accuracy slows protein synthesis so overall growth is slower. When you put the threonine or asparagine rspL 42 mutant streptomycin resistant bacteria and wild type streptomycin sensitive bacteria together in head to head competition in the absence of streptomycin, the wild type will out compete-them. It's a classic trade off, make your proteins carefully and grow slowly, or grow quickly and have some messed up proteins.

Importantly, not all mutations produce fitness costs. There are several examples of mutations that produce no fitness cost, or are even fitter than the wild-type antibiotic sensitive bacteria (Andersson, 1996; Zhang 2006).

Equally importantly, compensatory mutations occur that restore the fitness of the bacteria to wild type levels. There are multiple examples of this for streptomycin (Bjorkmann, 1996, 2000; Anderson, 2006) and other antibiotics (Anderson, 2006; Maisnier-Patin, 2002; Zhang 2006). This is a major issue in clinical treatment, as it means that withdrawing use of an antibiotic does not mean that the antibiotic resistant bacteria will go away.

Finally, as discussed elsewhere, mutations in the regions of non-coding DNA that act as genetic switches, CREs, have significantly lower fitness penalties than mutations in protein-coding regions of developmental regulatory genes.

References:

Andersson DI. The biological cost of mutational antibiotic resistance: any practical conclusions?Curr Opin Microbiol. 2006 Oct;9(5):461-5. Epub 2006 Aug 4.

Bjorkman J, Hughes D, Andersson DI. Virulence of antibiotic-resistant Salmonella typhimurium. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3949-53

Bjorkman J, et al., Novel ribosomal mutations affecting translational accuracy, antibiotic resistance and virulence of Salmonella typhimurium. Mol Microbiol. 1999 Jan;31(1):53-8

Bjorkman J, Nagaev I, Berg OG, Hughes D, Andersson DI. Effects of environment on compensatory mutations to ameliorate costs of antibiotic resistance. Science. 2000 Feb 25;287(5457):1479-82

Maisnier-Patin S, Berg OG, Liljas L, Andersson DI. Compensatory adaptation to the deleterious effect of antibiotic resistance in Salmonella typhimurium. Mol Microbiol. 2002 Oct;46(2):355-66

Sideraki V, Huang W, Palzkill T, Gilbert HF. A secondary drug resistance mutation of TEM-1 beta-lactamase that suppresses misfolding and aggregation. Proc Natl Acad Sci U S A. 2001 Jan 2;98(1):283-8.

Wu S, Piscitelli C, de Lencastre H, Tomasz A. "Tracking the evolutionary origin of the methicillin resistance gene: cloning and sequencing of a homologue of mecA from a methicillin susceptible strain of Staphylococcus sciuri." Microb Drug Resist. 1996 2(4):435-4

Wu SW, de Lencastre H, Tomasz A. "Recruitment of the mecA gene homologue of Staphylococcus sciuri into a resistance determinant and expression of the resistant phenotype in Staphylococcus aureus." J Bacteriol. 2001 Apr;183(8):2417-24

Zhang Q, Sahin O, McDermott PF, Payot S. "Fitness of antimicrobial-resistant Campylobacter and Salmonella." Microbes Infect. 2006 Jun;8(7):1972-8. Epub 2006 Mar 31.

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