Confessions of a superbug - how GES-5 didn't evolve

In the past, bacterial infections were very dangerous and often fatal conditions. The situation improved considerably in 1942, when penicillin was first used clinically as an antibiotic. But unfortunately, the bugs struck back. Bacteria can become resistant to antibiotics. Such bacteria are sometimes called “superbugs” in the lay press.

How does a bacterium acquire antibiotic resistance? Many mechanisms have been identified, but here, we will consider one specific example of acquired antibiotic resistance: Guiana extended-spectrum, or GES-5.

GES-5 encodes for an unusually potent carbapenemase

Carbapenems are a class of antibiotics with very broad antimicrobial activity. They are usually reserved for the treatment of highly resistant organisms. For this reason, bacteria that acquire resistance to carbapenems are of particular concern. A number of bacterial genes can indeed confer such resistance, and the proteins they specify are broadly referred to as Class A carbapenemases. These gene families include GES, KPC, SME, IMI/NMC-A, SHV-38 and SFC-1.¹

GES-5 is a gene that specifies a particularly interesting (or frightening, depending on whether you are reading about it or actually infected with it) carbapenemase. GES-5 has a specific point mutation that encodes for the amino acid serine at position 170 in the protein molecule. Ser-170 results in a dramatically enhanced rate of deacylation, the chemical reaction responsible for carbapenem resistance. The difference is dramatic: GES-5 demonstrates a 5000-fold and 1500-fold increase in the rate constant over GES-1 and GES-2 respectively.²

How did GES-5 come to be? Because the increased enzymatic activity of this carbapenemase is conferred by a point mutation, we might imagine that this mutation was a random one, upon which natural selection subsequently acted. If true, that would represent microevolution. But in fact, that isn’t the case.

Where did GES-5 come from?

GES-5 has been separately isolated in Greece, Korea, Brazil, China and South Africa. It always occurs as part of the variable region of a specific genomic locus called a class 1 integron. An integron is a group of related genes that facilitates the horizontal gene transfer, or HGT, of genetic material from one bacterium to another. The transfer of such mobile genetic elements, or MGE’s, is “the major contributor to emergence, recombination and dissemination of multidrug resistance among bacterial pathogens.”^3,^4,⁵ Vehicles for exchange of MGE’s include “plasmids, bacteriophages, genomic islands (GIs), integrative and conjugative elements (ICEs), insertion sequences (ISs), transposons (Tns), integrons and miniature inverted repeat transposable elements (MITES).^6,⁷ The genes so transferred are commonly referred to as a gene cassette.

In the case of GES-5, an integron facilitates the horizontal transfer of the gene cassette. In fact, “all blaGES-type genes described to date occurred as part of integron structures on mobile transmissible genetic elements.”⁸

What does this really mean?

The GES-5 gene is not the result of a random mutation in a bacterium that “got lucky.” It is always found in a specific genomic location that was designed to receive genes from another bacterium. Integrons always include several specific genes at a minimum:

An intI gene specifying a protein recombinase that inserts the contents of the gene cassette into the genome in a specific location where they can be utilized.
An attI recombination site, the specific genomic location mentioned above.
A Pc promoter that directs the transcription of these other genes.

Bacteria containing the GES-5 gene have been isolated from all over the world. But like all GES genes, GES-5 is always found within an integron. This common pattern is highly suggestive:

Identical integron structures in unrelated, geographically scattered isolates may indicate a common ancestor or natural producer of GES-type ESBLs.⁹

Neither of these scenarios is good news for evolutionists. Why not?

Integrons are cohesive genomic structures that always contain the same specific regulatory components necessary for their function, in addition to a variable region containing the specific genes that have been incorporated. As such, they are strongly emergent constructs that require top-down design, as we have noted elsewhere.
If all the integrons in all the bacteria around the world have a common ancestor, this would imply that integrons have never undergone any evolutionary change whatsoever, but have instead been meticulously conserved across perhaps one trillion microbial species.¹⁰
If there is a natural producer of GES-type ESBLs (a far more likely explanation) then no evolution is required. Bacteria simply have the capacity to share GES genes via HGT by virtue of the ubiquitous presence of integrons in their genomes.

Of course, this third observation alludes to a more broadly relevant question about evolution in general. If bacteria around the world have acquired the genes for antibiotic resistance from each other by means of HGT, where did the genes they are sharing ever come from to begin with?

For the answer, let us consult the literature:

While the origin of the gene cassettes is a fascinating question, essentially no pertinent information is currently available. Any pathway proposed for cassette creation must necessarily account for all of their features, namely that cassettes normally include a single complete gene and, as the orientation of the cassettes is determined by the 59-base element, a correctly oriented 59-base element at the 3' end of the gene.¹¹

Living things do not evolve; rather, they live by virtue of cohesive genomes of extraordinary and emergent complexity. The GES-5 gene, incorporated into the integron segments of various microbial genomes around the world, bears further witness to life’s brilliant design.

Walther-Rasmussen, J, and N Høiby. “Class a Carbapenemases.” J Antimicrob Chemother 60.3 (2007): 470-82. ↩︎
Frase, H, Q Shi et al. “Mechanistic Basis for the Emergence of Catalytic Competence Against Carbapenem Antibiotics By the Ges Family of Beta-Lactamases.” J Biol Chem 284.43 (2009): 29509-13. ↩︎
Domingues, S, GJ da Silva, and KM Nielsen. “Integrons: Vehicles and Pathways for Horizontal Dissemination in Bacteria.” Mob Genet Elements 2.5 (2012): 211-23. ↩︎
Nakamura Y, Itoh T, Matsuda H, Gojobori T. Biased biological functions of horizontally transferred genes in prokaryotic genomes. Nat Genet 2004; 36:760-6. ↩︎
Thomas CM, Nielsen KM. Mechanisms of and barriers to, horizontal gene transfer between bacteria. Nat Rev Microbiol 2005; 3:711-21. ↩︎
Domingues, S, GJ da Silva, and KM Nielsen. “Integrons: Vehicles and Pathways for Horizontal Dissemination in Bacteria.” Mob Genet Elements 2.5 (2012): 211-23. ↩︎
Stokes HW, Gillings MR. Gene flow, mobile genetic elements and the recruitment of antibiotic resistance genes into Gram-negative pathogens. FEMS Microbiol Rev 2011; 35:790-819. ↩︎
Labuschagne, Cde J, GF Weldhagen et al. “Emergence of Class 1 Integron-Associated Ges-5 and Ges-5-like Extended-Spectrum Beta-Lactamases in Clinical Isolates of Pseudomonas Aeruginosa in South Africa.” Int J Antimicrob Agents 31.6 (2008): 527-30. ↩︎
Labuschagne, Cde J, GF Weldhagen et al. “Emergence of Class 1 Integron-Associated Ges-5 and Ges-5-like Extended-Spectrum Beta-Lactamases in Clinical Isolates of Pseudomonas Aeruginosa in South Africa.” Int J Antimicrob Agents 31.6 (2008): 527-30. ↩︎
We will leave the challenge of explaining what selection pressure could drive such tremendous diversification, even while preserving the genomic organization of the integron, to the evolutionists. ↩︎
Hall, Ruth M, and Christina M Collis. “Mobile Gene Cassettes and Integrons: Capture and Spread of Genes By Site‐specific Recombination.” Molecular microbiology 15.4 (1995): 593-600. ↩︎