The use of lifesaving antibiotics can unfortunately run the risk of increasing antibiotic resistance, which is a leading global health threat. One example of this is the use of daptomycin (DAP), a last resort intravenous (IV) antibiotic used to treat multidrug resistant bacteria; about 5-10% of DAP administered can end up in the gastrointestinal (GI) tract, leading opportunistic bacteria to develop resistance without therapeutic gain, explained Amir Sheiki, an assistant professor of chemical engineering at Penn State. Penn State researchers have now discovered a potential means of lowering the risk of antibiotic resistance developing from DAP treatment, uncovering the mechanisms behind the removal of DAP from the GI tract by the cholesterol drug cholestyramine.
Cholestyramine is an oral drug approved by the U.S. Food and Drug Administration (FDA) to reduce cholesterol levels and remove bile acids associated with liver disease. The drug is an ion exchange biomaterial (IXB) sorbent and has previously been shown to prevent DAP resistance in 84% of mice in in vivo experiments. However, the exact mechanism through which cholestyramine prevented resistance was not revealed in these previous experiments. In the recent study, the researchers used a combination of techniques including imaging and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy to examine the IXB-mediated capture of DAP from both pH and electrolyte-controlled aqueous solutions and simulated intestinal fluid.
DAP is an amphiphilic molecule that undergoes molecular self-assembly. The team’s experiments showed that cholestyramine electrostatically attracts the negatively charged DAP to its surface, after which DAP adsorbs into the IXB, disassembles and diffuses into the sorbent within hours. As a complex with cholestyramine, DAP is no longer treated as a threat by bacteria and thus the bacteria do not develop DAP resistance. The researchers also found that the IXB’s maximum capacity to remove DAP was 200% greater than the theoretical level of removal in which one DAP molecule could be removed per active site of the IXB. The self-assembly process of DAP produces aggregates in aqueous solutions, so more than one DAP molecule can be removed per active site. Captured DAP passes through the body together with the IXB and it takes about four hours for cholestyramine to reach maximum DAP removal capacity, removing nearly 100% of the DAP, said Sheikhi. This research was published in ACS Applied Materials & Interfaces.
“This work lays the foundations for optimizing the use of IXBs, such as cholestyramine, as adjuvant therapy to prevent DAP resistance, as well as designing next-generation biomaterials that may combat the emergence of antimicrobial resistance in the GI tract,” said Sheikhi. “Antibiotic development costs significant time and money, only to eventually be resisted. Our new understanding could help us keep our current antibiotics working properly.”
The researchers hope to continue their work and eventually conduct clinical testing of the effectiveness of IXBs for DAP removal in humans.