Friday, June 15, 2007

Penicillin Resistance in Bacteria: After 1960

The widespread appearance of penicillin-resistant bacteria by 1960 prompted the introduction of new drugs that could not be degraded by newly evolved β-lactamases [see Penicillin Resistance in Bacteria: Before 1960].

The most important of these new drugs are the cephalosporins, modified β-lactams with bulky side chains at two different positions. These drugs still inhibit the transpeptidases and prevent cell wall formation but because of the bulky side chains they cannot be hydrolyzed by β-lactamases. Thus, they are effective against most of the penicillin-resistant strains that arose before 1960.

Other drugs, such as methicillin, were modified penicillins. They also had modified side chains that prevented degradation by the β-lactamases.

It wasn't long before cephalosporin- and methicillin-resistant strains began to appear in hospitals. As a general rule, these strains were not completely resistant to high doses of the new class of drugs but as time went on the resistant strains became more and more immune to the drugs.

The new version of drug resistance also involves the transpeptidase target but instead of developing into β-lactamases they evolve into enzymes that can no longer bind the cephalosporins. Usually the development of resistance takes place in several stages.

There are many different transpeptidases in most species of bacteria. The are usually referred to as penicillin-binding proteins or PBP's. Often the first sign of non-lactamase drug resistance is a mutant version of one PDP (e.g., PDP1a) and subsequent development of greater resistance requires the evolution of other PDB's that don't bind the drug. In the most resistant strains there will be one particular PDB (e.g., PDB2a) that is still active at high drug concentrations while the other transpeptidases will be inhibited.

Resistant enzymes have multiple mutations, which explains the slow, stepwise acquisition of drug resistance. An example is shown in the figure. This is PDP1a from Streptococcus pneumoniae (Contreras, et al. 2006) and the mutant amino acids are displayed as gold spheres. Most of the mutations do not affect the binding of the drug but those surrounding the entry to the active site are crucial. The necessary amino acid substitutions are numbered in the figure. You can see that they line the groove where the cephalosporin drug (purple) is bound. The effect of the mutations is to prevent the bulky β-lactam from inhibiting the enzyme. This is a very different form of drug resistance than the evolution of degradation enzymes that characterized the first stage of penicillin resistant bacteria.

Chambers, H.F. (2003) Solving staphylococcal resistance to beta-lactams. Trends Microbiol. 11:145-148.

Contreras-Martel, C., Job, V., Di Guilmi, A.M., Vernet, T., Dideberg, O. and Dessen, A. (2006) Crystal structure of penicillin-binding protein 1a (PBP1a) reveals a mutational hotspot implicated in beta-lactam resistance in Streptococcus pneumoniae. J. Mol. Biol. 355:684-696.

Livermore, D.M. (2000) Antibiotic resistance in staphylococci. Int. J. Antimicrob. Agents 16:s3-s10.


  1. Slightly off-topic, but it concerns evolution and atheism, so I thought you might be interested. I came across this blog article entitled "G-d is Greater Than Christoper Hitchens": I don't normally read this person's work, as I think he's hateful, stereotypical, etc.; however, I was compelled to read this particular blog entry for probably obvious reasons, and I figured that since it concernes evolutionary theory, you might be interested as well.

    (I've also posted a response at, which I co-write)

  2. Yeas I think same "Most bacterial species are either spherical, called cocci (sing. coccus, from Greek kókkos, grain, seed) or rod-shaped, called bacilli (sing. bacillus, from Latin baculus, stick). Elongation is associated with swimming.[34] Some rod-shaped bacteria, called vibrio, are slightly curved or comma-shaped; others, can be spiral-shaped, called spirilla, or tightly coiled, called spirochaetes. A small number of species even have tetrahedral or cuboidal shapes.[35] More recently, bacteria were discovered deep under the Earth's crust that grow as long rods with a star-shaped cross-section. The large surface area to volume ratio of this morphology may give these bacteria an advantage in nutrient-poor environments.[36] This wide variety of shapes is determined by the bacterial cell wall and cytoskeleton, and is important because it can influence the ability of bacteria to acquire nutrients, attach to surfaces, swim through liquids and escape predators"