Accumlation of antiobiotic sensitivity

[CharonY]

In this very interesting paper it is indicated that at least in Pseudomonas aeruginosa anitbiotic sensitivity accumlates faster than resistance. This indicates that there might not be a trend for accumlation of resistances.

Quite the contrary as usually expected!

 

Antibiotic resistance is a pervasive and growing clinical problem. We describe an evaluation of a reverse engineering approach for identifying cellular mechanisms and genes that could be manipulated to increase antibiotic sensitivity in a resistant Pseudomonas aeruginosa isolate. We began by chemically mutating a broadly resistant isolate of P. aeruginosa and screening for mutants with increased sensitivity to the aminoglycoside amikacin, followed by performing whole-genome transcriptional profiling of the mutant and wild-type strains to characterize the global changes occurring as a result of the mutations. We then performed a series of assays to characterize the mechanisms involved in the increased sensitivity of the mutant strains. We report four primary results: (i) mutations that increase sensitivity occur at a high frequency (10–2) relative to the frequency of those that increase resistance (10–5 to 10–10) and occur at a frequency 104 higher than the frequency of a single point mutation; (ii) transcriptional profiles were altered in sensitive mutants, resulting in overall expression patterns more similar to those of the sensitive laboratory strain PAO1 than those of the parental resistant strain; (iii) genes found from transcriptional profiling had the more dramatic changes in expression-encoded functions related to cellular membrane permeability and aminoglycoside modification, both of which are known aminoglycoside resistance mechanisms; and finally, (iv) even though we did not identify the specific sites of mutation, several different follow-up MIC assays suggested that the mutations responsible for increased sensitivity differed between sensitive mutants.

 

Antimicrobial Agents and Chemotherapy, July 2006, p. 2506-2515, Vol. 50, No. 7

[Quentin]

It's an interesting paper. It shows us well the darwinian concept of selection. Bacterias which mute when they are cultivated with an antibiotic are defective bacterias compared to the wild type. But it's better for the bacteria to be defective and survey than to be killed by the antibiotic.

We can probably think that we could obtain a reversion in the mechanism of antibiotics resistance (a priority for the WHO, by the way...)... But it's maybe more complicated than it seems. Some resistance ways creates bacterias which seems to be not so defective : e.g. the Staphylococcus aureus and the resistance to Penicillin. A penicillinase is enough ! And after the begining of the antibiotherapy, the penicillin resistance came quickly ! But we can think that we could obtain a reversion in the resistance to oxacillin (or meticillin as you want) because the mechanism is a modification of the proteins which bind the penicillins (PLP2a), and a modification of the peptidoglycan is worse than secreting a little enzym.

Maybe by stopping using oxacillim, we may find a solution in the fight against MRSA ? The problem is that it implys treating MSSA without oxacillin (are we going to give vancomycin to everyone !?!)

The problem is not so easy... We do not have enough antibiotics. But we can say that there are probably two groups :

- resistance linked to a little modification of the bacteria (secreting an enzym, as the penicillinase and so on... or maybe more, considering TEM 3 or TEM 17, which are large spectrum beta lactamases...) ==> No easy reversion, because the bacteria is not so defective

- resistance liked to a big modification of the bacteria (like creating a new structure protein, mechanism of the oxacillin resistance for MRSA) ==> Easy reversion, because the bacteria is defective.