A new Trojan horse approach could lead to treatments for some antibiotic-resistant bacteria.

A deadly, antibiotic-resistant bacterium can be sterilized by hijacking its haem-acquisition system, which is essential for its survival. The new strategy, developed by Nagoya University researchers and colleagues in Japan, was published in the journal ACS Chemical Biology.

Pseudomonas aeruginosa is a dangerous bacterium that causes infections in hospital settings and in people with weakened immune systems. It can cause blood infections and pneumonia, while severe infections can be deadly. Highly resistant to antibiotic treatment, P. aeruginosa is one of the most critical pathogens urgently requiring alternative treatment strategies, according to the World Health Organization.

This bacterium is one of many that have evolved a system that allows them to acquire difficult-to-access iron from the human body. Iron is essential for bacterial growth and survival, but in humans, most of it is held up within the 'haem' complex of haemoglobin. To get hold of it, P. aeruginosa and other bacteria secrete a protein, called HasA, which latches onto haem in the blood. This complex is recognized by a membrane receptor on the bacterium called HasR, permitting haem entry into the bacterial cell, while HasA is recycled to pick up more haem.

Bioinorganic chemist Osami Shoji of Nagoya University and collaborators have found a way to hijack this 'haem acquisition system' for drug delivery. They developed a powder formed of HasA and the pigment gallium phthalocyanine (GaPc), which, when applied to a culture of P. aeruginosa, was consumed by the bacteria.

"When the pigment is exposed to near-infrared light, harmful reactive oxygen species are generated inside the bacterial cells," explains Shoji. When tested, over 99.99% of the bacteria were killed following treatment with one micromolar of HasA with GaPc and ten minutes of irradiation.

The strategy also worked on other bacteria with the HasR receptor on their membranes, but not on ones without it.

The haem acquisition system is so essential to these bacteria's survival that it is not expected to change, making it unlikely the bacteria will develop resistance to this drug strategy, the researchers believe.

"Our findings support the use of artificial haem proteins as a Trojan horse to selectively deliver antimicrobials to target bacteria, enabling their specific and effective sterilization, irrespective of antibiotic resistance," the team reports in their study.

Image: A solution of the extracellular heme acquisition system protein A (HasA) with gallium phthalocyanine (Left) and the results of sterilization of Pseudomonas aeruginosa and Escherichia coli treated with HasA-bound gallium phthalocyanine by irradiation with near-infrared light (Right).

Credit: Osami Shoji

The researchers next aim to test their strategy for treating infections, and are working on modifying their approach for sterilizing other pathogens that possess a similar haem acquisition system.

The article, "Hijacking the Heme Acquisition System of Pseudomonas aeruginosa for the Delivery of Phthalocyanine as an Antimicrobial," has been published in ACS Chemical Biology at DOI: 10.1021/acschembio.9b00373

Authors: Yuma Shisaka, Yusuke Iwai, Shiho Yamada, Hiromu Uehara, Takehiko Tosha, Hiroshi Sugimoto, Yoshitsugu Shiro, Joshua K. Stanfield, Kazuya Ogawa, Yoshihito Watanabe and Osami Shoji

Researcher Contact Details

Professor Osami Shoji

Nagoya University

shoji.osami@a.mbox.nagoya-u.ac.jp

http://bioinorg.chem.nagoya-u.ac.jp/en/index.html

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About Nagoya University

Nagoya University has a history of about 150 years, with its roots in a temporary medical school and hospital established in 1871, and was formally instituted as the last Imperial University of Japan in 1939. Although modest in size compared to the largest universities in Japan, Nagoya University has been pursuing excellence since its founding. Six of the 18 Japanese Nobel Prize-winners since 2000 did all or part of their Nobel Prize-winning work at Nagoya University: four in physics - Maskawa and Kobayashi in 2008, and Akasaki and Amano in 2014 - and two in Chemistry - Noyori in 2001 and Shimomura in 2008. In mathematics, Mori did his Fields Medal-winning work at Nagoya University. A number of other important discoveries have been made at Nagoya University, including the Okazaki DNA Fragments by Reiji and Tsuneko Okazaki in the 1960s; and depletion forces by Asakura and Oosawa in 1954.