Beta-lactam antibiotics, penicillin and all of its subsequent derivatives, are critical, life saving drugs. One way bacteria protect themselves from these antibiotics is by producing enzymes known as beta-lactamases that cleave the beta-lactam, rendering the beta-lactam antibiotic harmless. There are many different kinds of beta-lactams (such as CTX-M), and they differ in how common or rare they are.
A recent study examined looked at the role fitness might have in making TEM class beta-lactamases very frequent and found in many different species, and keeping SME class beta-lactamases rare and limited mostly to one organism, Serratia marcescens (hence the name ‘SME’ for the class). These different distributions are all the more puzzling because the most common forms of TEM beta-lactamases confer resistance only to amoxicillin (ampicillin), whereas the SME beta-lactamases confer resistance to most beta-lactams including carbapenems, the most advanced form of beta-lactams.
In the study, two bacterial strains of E. coli were constructed that were genetically identical except that one contained a plasmid with a TEM-1 gene, and the other contained a plasmid with an SME-1 gene (other than this, the plasmids were identical). When the two strains were grown in competition with each other in the absence of antibiotic, the TEM-1 strain grew faster. Not only did the TEM-1 strain grow faster, but many different mutational events that prevented the SME-1 beta-lactamase from being made were observed in the SME-1 strain. So it would appear there is strong selection against the SME-1 beta-lactamase when antibiotics are not present.
The researchers then tried to determine what was the cause of this fitness (co-cultured growth rate) difference. What they found was that a significant cause of the fitness difference was due to the SME-1 signal peptide, the initial part of the protein that is removed during protein production, and not a part of the working beta-lactamase (the SME-1 beta-lactamase protein also seems to lower fitness). If you remember cassette tapes, this would be like that white part at the beginning of the tape suddenly playing music.
It’s intriguing to think that one of the important, and currently unrecognized, factors in the successful spread of a resistance gene might not be function of the gene per se, but other components such as manufacture and protein stability.
Cited article:</b> David C. Marciano, Omid Y. Karkouti, and Timothy Palzkill. A Fitness Cost Associated With the Antibiotic Resistance Enzyme SME-1 ß-Lactamase. Genetics 2007 176: 2381-2392. doi:10.1534/genetics.106.069443
“It was the best of enzymes, it was the worst of enzymes.”
There’s also a French resistance joke in there somewhere…
I banged my head against the wall trying to figure out what was behind the fitness cost of SME-1. After a long list of failed hypotheses, it was the power of genetics and a little fishing expedition that saved the day and led me to the signal sequence.