The “magic bullet” misses its target-how does this happen?

antibiotic resistance (cartoon)-resize

A failing promise-
They were called “magic bullets”- antibiotics, once held sacred as the panacea that would cure almost all kinds of infectious diseases. Their continued success is reflected by the decrease in the morbidity of bacterial infections during the past few decades. However, the increasing misuse of antibiotics for human and non-therapeutic animal treatment have led to greater and greater resistance, in a phenomenon that has become a serious worldwide concern for health care systems.

The mysteries of initial resistance –
While there are a number of known resistance mechanisms that develop in bacteria, the series of steps and molecular mechanisms that lead bacteria from being antibiotic susceptible to antibiotic resistant still remain unclear. The prevailing view has been that resistance arises from the spontaneous mutation of individual bacteria, though recent research suggests that the process is not this simplistic. Recently, we published a novel view of this development ( In our research, we chose Pseudomonas aeruginosa, which is an opportunistic pathogen, and the antibiotic “ciprofloxacin” as our study subjects. P. aeruginosa is responsible for many chronic lung infections and 10% of hospital-acquired infections; and when repeatedly treated by ciprofloxacin (a commonly used antibiotic for P. aeruginosa infection), this organism rapidly acquires high-level resistance. To shed light on P. aeruginosa’s proclivity for quickly developing new defenses, we set out to investigate the development of initial resistance using a proteomics and genomics approach. In vivo cultures were supplemented by mathematical modeling to simulate the resistance development process in P. aeruginosa.

What we have learned from our study-
We found that when continuously exposed to ciprofloxacin for up to 48 hours, P. aeruginosa acquired drug resistance in a multistage process. The drug is initially very effective at killing susceptible P. aeruginosa. However, a tolerant/ persistent subpopulation survives and soon emerges to reconstitute the population with significantly increased antibiotic resistance. Our resistance distribution assay and mathematical model suggest that this resistance is not the result of a preexisting mutant in the population. Further, our proteomics assay data indicate that preexisting cellular pathways may support the resistance development process, too. Considering these results, it appears that the development of high level resistance in P. aeruginosa is a stepwise fine-tuning process, not one simply caused by an all-at-once single gene mutation.

More detail-
Please find more information at ( Feel free to contact us if you have questions or are interested in further collaboration. Thanks.

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