Two weeks ago, the World Health Organisation (WHO) announced its first list of antibiotic-resistant "priority pathogens" that experts say pose the greatest threat to human health. These superbugs cause the death for millions of people every year and will increase in number if the issue is not addressed quickly.

Many researchers have been on the hunt for new antibiotics or experimenting different methods to combat the global problem. Now, two separate teams have found one-two punch strategies to combat the bacteria that are immune to penicillin and colistin.

Penicillin-immune bacteria release enzymes called beta-lactamases that breakdown the antibiotics - allowing them to be immune to antibiotics such as amoxicillin and ampicllin. Some bacteria can defeat even newly developed penicillins by excreting metallo-beta lactamases (MBLs), allowing immunity to carbapenem, causing fatal infections.

One-two punch effective against CREs

In a study led by Robert A. Bonomo from Case Western Reserve University School of Medicine in Cleveland, Ohio, has discovered that combining two antibiotics eliminated 81% of carbapenem-resistant eneterobacteriaceae (CRE) specimens.

The first antibiotic, called ceftazidime/avibactam, is sensitive towards MBLs, but not other enzymes secreted by the superbugs. The second, called aztreonam, is instead vulnerable to other CRE enzymes but is effective against MBLs. Together, the antibiotics run interference for each other, delivering an effective one-two punch to defeat the CRE infection.

"Aztreonam skirts around the MBL and hits its target - the penicillin-binding proteins," Bonomo explained. This cripples the bacteria, unable to build effective cell walls, and they quickly die. The combination might enable doctors and patients to overcome the antibiotic neutralising MBLs.

The therapy was shown to work in the lab and in two patients who were not responding to the standard courses of treatment. Lab results were successful and both patients survived. The team is looking to further clinical testing and research before the method is released for common use.

"If we understand the fundamental mechanisms by which bacteria become resistant to antibiotics, we can use what we know to help design better therapies," Bonomo said.

Drug therapy against "priority pathogens" might be available

Separately, scientists from McMaster University have developed a similar one-two punch strategy, but focused on Gram-negative bacteria which are resistant to all antibiotics, including last resort drugs, such as colistin.

"We looked for compounds that would mess with these bacteria, and I think we're nailing it," said Eric Brown, senior author of the paper, a professor of biochemistry and biomedical science at McMaster's Michael G. DeGroote School of Medicine and a scientist of the Michael G. DeGroote Institute for infectious Disease Research.
The team discovered that antiprotozoal drug pentamidine, disrupts the cell surface of Gram-negative bacteria and was particularly effective when used with antibiotics against superbugs.

They were found to be particularly effective against two of the three pathogens - Acinetobacter baumannii and enterobacteriaceae - that the WHO has listed in their list. The combination also affected the third most critical bacteria, Pseudomonas aeruginosa.

The team tested the therapy in the lab and on mice, but agreed that more work is needed to determine any potential side effects to ensure safety, much like the Case Western Reserve team.

"One of the things we want to pursue further is why this is working so well," Brown said. MIMS

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