Alternating Antibiotics Eliminate Drug-Resistant Bacteria

A new technique has been pioneered to help combat the rise of antibiotic-resistant bacteria that cause debilitating and often life-threatening human illness.

The technique uses sequential treatments, alternating doses of antibiotics which might offer effective treatment against bacterial infection. This technique demonstrates that by administering sequential treatment also reduces the risk of the bacteria becoming resistant to antibiotics, and so maintaining the long-term effectiveness of the drugs.

Scientists at the University of Exeter (UK) working with colleagues in Mexico and Germany showed that sequential treatments can clear the bacterium when the equivalent combination treatment fails to, provided, that is, that the drugs are deployed in a suitably optimized, sequential manner. To demonstrate this, they used the following laboratory system: Escherichia coli K12 (AG100) was targeted with two antibiotics, erythromycin (a macrolide, ERY) and doxycycline (a tetracycline, DOX), that bind to different ribosomal RNA subunits, thereby inhibiting translation. While this is a nonclinical drug pairing, the commercial drug Synercid (comprising quinupristin and dalfopristin) also targets ribosomal RNA combinatorially.

After increasing dosages to their 70% inhibitory concentration (IC70) values, the following evidence of bacterial clearance by 96 hours was observed. Sixteen sequential treatments that produced some of the lowest population densities after 96 hours of treatment were examined, and, using spot tests, no live cells could be isolated for five of these treatments in all three replicates. In order to determine genetic changes due to the differential stresses found in drug-free conditions and in the sequential and combination treatments, two treatments at half maximal inhibitory concentration (IC50) that produced comparable densities at 96 hour were subjected to a whole-genome sequencing analysis and compared to the drug-free populations. All replicate populations from 24 hours and 96 hours were sequenced using the paired end technology on the ABI 7500 real time polymerase chain reaction system machine (Applied Biosystems; Grand Island, NY, USA).

Robert Beardmore, PhD, a professor and lead author of the study, said, “Our study finds a complex relationship between dose, bacterial population densities and drug resistance. As we demonstrate, it is possible to reduce bacterial load to zero at dosages that are usually said to be sub lethal and, therefore, are assumed to select for increased drug resistance.” The study was published on April 8, 2015, in the journal Public Library of Science Biology.

Related Links:
University of Exeter 
Applied Biosystems