Friday, 28 July 2017 19:00

Little cross-resistance observed in clinical colistin-resistant isolates

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Published in mBiosphere

Colistin resistance is an emerging concern in clinical infectious disease. Colistin, once shelved due to kidney toxicity associated with its use, has become one of the last-resort drugs, due to its ability to treat otherwise nonresponsive bacterial infections. Not surprisingly, increased clinical use has produced an increasing number of resistant isolates. But slightly more promising news was revealed in a recent Antimicrobial Agents and Chemotherapy report, demonstrating that colistin resistance does not confer cross-resistance to antimicrobial peptides or ceragenins.

AAC: Susceptibility of colistin-resistant, gram-negative bacteria to antimicrobial peptides and ceragenins

To understand this result, it’s important to first remember how bacteria become resistant to colistin. Colistin (also called polymyxin E) fights bacterial infection due to its cationic properties. The positively-charged colistin interacts with the negatively-charged bacterial envelope, disrupting the ionic balance of the cell. The widely reported mcr-1 gene product, a phosphatidylethanolamine (PE) transferase, adds a neutrally-charged PE residue to the negatively charged lipid A of gram-negative bacteria, reducing the drug-bacteria interaction. Other resistance mechanisms also involve lipid A modifications to mask its charge.

Host antimicrobial peptides (AMPs) are part of the host defense against bacteria and many AMPs also disrupt bacterial membrane homeostasis through charged interactions. Ceragenins are chemically derived AMP mimetics that have similar mechanisms but are more easily scaled up for production, leading some researchers to propose their use as infection-fighting agents. Because AMPs, ceragenins and colistin all interact with bacteria via charged interactions, the scientific team led by first author Marjan Hashemi and senior scientist Paul Savage wanted to know if colistin-resistant clinical isolates are also resistant to AMPs.

Colistin cross resistance tableMICs of colistin, AMPs, and caragenins against a standard K. pneumoniae strain (ATCC 13883) and colistin-resistant clinical isolates. Source.

They tested susceptibility of colistin-resistant Klebsiella pneumoniae, one of the ESKAPE pathogens, to colistin, three different AMPs, and five caragenins, and compared this susceptibility to that of a colistin-sensitive lab strain. As expected, the minimal inhibitory concentration (MIC) of colistin was eight- to 100-fold higher in the resistant clinical isolates. The MIC of AMPs or caragenin molecules either remained the same, or increased two- to fivefold (see table, right). This demonstrates that these molecules largely remain effective against colistin-resistant K. pneumoniae, and supports the development of caragenins for clinical use.

The researchers didn’t investigate the genetic basis of colistin resistance, but did observe a variety of lipid A modifications in the isolates, suggesting distinct mechanisms conferred resistance for each strain. All three molecular classes target lipid A, but this work implies AMP/caragenin interactions with the bacterial membrane differs from colistin/membrane interactions in a manner that can be utilized by researchers.

The news isn’t all good, however. Studies are mixed, with some demonstrating cross-resistance of colistin-resistant Acinetobacter baumannii to host AMP molecules, and others demonstrating efficacy of host AMP against a variety of colistin-resistant gram-negative bacteria. Because the interactions involve different host molecules, bacterial species, and resistance mechanisms, the case isn’t closed on how colistin resistance affects the activity of these host molecules. The current report bodes well, however, for the resilience of caragenins and their future applications.

K. pneumoniae photo credit

Last modified on Friday, 28 July 2017 19:27
Julie Wolf

Julie Wolf is the ASM Science Communications Specialist. She contributes to the ASM social media and blog network and hosts the Meet the Microbiologist podcast. She also runs workshops at ASM conferences to help scientists improve their own communication skills. Follow Julie on Twitter for more ASM and microbiology highlights at @JulieMarieWolf.

Julie earned her Ph.D. from the University of Minnesota, focusing on medical mycology and infectious disease. Outside of her work at ASM, she maintains a strong commitment to scientific education and teaches molecular biology at the community biolab, Genspace. She lives in beautiful New York City.