Pre-Existing Resistance

All antibiotic resistance that develops in bacteria can be traced back to mutations in bacteria that were originally susceptible to antibiotics. Explore Evolution is rather incoherent in its discussion of antibiotic resistance. It incorrectly presents antibiotic resistance as due to pre-existing coding in the bacterial population for different varieties of beta-lactamase (an enzyme that breaks down penicillin).

Explore Evolution claims:

In the case of penicillin resistance, critics agree that when penicillin is present in the bloodstream, a bacterial strain that already has a gene coding for penicillinase will have a significant survival advantage over a strain that doesn't. They do not develop such a gene when penicillin is introduced.
Explore Evolution, p. 102

Before discussing the origin of antibiotic resistance further, a little background is required. Antibiotics revolutionised medicine. For example, prior to antibiotics, 82% of people infected with the bacteria Staphylococcus aureus died. After the introduction of penicillin in 1944, most people infected with this bacterium survived. However, by 1947 the first clinical case of S. aureus resistant to penicillin was described. By 1952, over 75% of S. aureus was resistant to penicillin. A similar history is seen with other antibiotics. Methicillin, an antibiotic developed to be resistant to beta-lactamases (the bacterial enzymes that break down penicillin), was introduced in the 1960 s, by the 1970 s the first reports of resistance to methicillin were coming in. Vancomycin, the antibiotic of last resort for organisms like S. aureus, was introduced in the mid-1950 s but bacterial resistance to vancomycin was first seen in the 1980's and in 2002 vancomycin resistant S. aureus were reported. As can be seen, antibiotic resistance in populations of bacteria develop after a lag phase of some years, which would not happen if antibiotic resistance was just selection of pre-existing variability.

Antibiotic resistance occurs in many ways (Patostini et al, 2007), some bacteria are resistant because they develop enzymes that break down antibiotics, such as the beta-lactamases that break down penicillin, others develop proteins that bind the antibiotics and prevent them acting on their targets, such as the penicillin-binding-proteins that inactivate methicillin, still others develop enzymes that bypass the biological process that the antibiotic targets, such as the alternative cell wall synthesis enzymes that evade vancomycin.

Still other mechanisms involve altering the ability of enzymes to bind the antibiotic, decreasing the antibiotics entry into the cell, or increasing the activity of cell membrane pumps which remove the antibiotic from the cell. Antibiotic resistant bacteria may utilise one or more of these mechanisms.

Antibiotic resistant bacteria gain these mechanisms in one of two ways. They may develop by mutation of one or more genes in previously antibiotic sensitive bacteria, or bacteria may gain resistance genes via horizontal gene transfer from bacteria that are already resistant.

However, the genes that have been transferred were originally the products of mutation. The methicillin resistance gene is a mutant duplicate of a gene that did not originally bind penicillin found in the widely distributed bacteria S. sciuri that was transferred to S. aureus (Wu et al., 1996, 2001). The vancomycin resistance gene is a mutant version of the D-ala-D-ala ligase cell wall synthesis enzyme that has been transfered from Enterococcus faecium to S. aureus. Only a single mutation is required to change the cell wall synthesis enzyme D-Ala-D-Ala ligase to the D-Ala-D-Lac ligase that is the vancomycin resistance gene product (Park et al., 1996).

Explore Evolution treats the variants of beta-lactamase as if they were always present and could not have been produced through mutations, whereas research shows that beta-lactamases are mutant versions of a variety of enzymes (one group are mutant D-ala-D-ala ligases, Knox et al., 1996). As these enzymes originated very early on, their evolutionary history is more obscure than that of the vancomycin or methicillin resistance genes. However, in the continuing arms race of humans versus bacteria, new beta-lactamase resistant antibiotics have been introduced, and new beta-lactamases have evolved that can break down these antibiotics. Generally, as newer variants of beta-lactam antibiotics have been introduced, beta lactamase variants active against those beta-lactams have appeared within 2 to 3 years. The study of these mutations is a classic in evolution research (Petrosino et al., 1998).

References:

Knox JR, Moews PC, and Frere JM, Molecular evolution of bacterial beta-lactam resistance, Chemistry & Biology 3, 1996, p. 937-947.

Park IS, Lin CH, Walsh CT. Gain of D-alanyl-D-lactate or D-lactyl-D-alanine synthetase activities in three active-site mutants of the Escherichia coli D-alanyl-D-alanine ligase B. Biochemistry. 1996 Aug 13;35(32):10464-71.

Pantosti A, Sanchini A, Monaco M. Mechanisms of antibiotic resistance in Staphylococcus aureus. Future Microbiol. 2007 Jun;2:323-34.

Petrosino J, Cantu C 3rd, Palzkill T. beta-Lactamases: protein evolution in real time. Trends Microbiol. 1998 Aug;6(8):323-7.

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):435-41

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.

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