Hijacking the Heme Acquisition System of Pseudomonas aeruginosa for the Delivery of Phthalocyanine as an Antimicrobial

• Published in: ACS chemical biology 2019-07, Vol.14 (7), p.1637-1642
• Main Authors: Shisaka, Yuma, Iwai, Yusuke, Yamada, Shiho, Uehara, Hiromu, Tosha, Takehiko, Sugimoto, Hiroshi, Shiro, Yoshitsugu, Stanfield, Joshua K, Ogawa, Kazuya, Watanabe, Yoshihito, Shoji, Osami
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacology; Bacterial Proteins - metabolism; Carrier Proteins - metabolism; Drug Carriers - metabolism; Drug Delivery Systems; Heme - metabolism; Humans; Indoles - administration & dosage; Indoles - pharmacology; Models, Molecular; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - metabolism; Pseudomonas Infections - drug therapy; Pseudomonas Infections - prevention & control
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.9b00373

To survive in the iron-devoid environment of their host, pathogenic bacteria have devised multifarious cunning tactics such as evolving intricate heme transport systems to pirate extracellular heme. Yet, the potential of heme transport systems as antimicrobial targets has not been explored. Herein we developed a strategy to deliver antimicrobials by exploiting the extracellular heme acquisition system protein A (HasA) of Pseudomonas aeruginosa. We demonstrated that, analogous to heme uptake, HasA can specifically traffic an antimicrobial, gallium phthalocyanine (GaPc), into the intracellular space of P. aeruginosa via the interaction of HasA with its outer membrane receptor HasR. HasA enables water-insoluble GaPc to be mistakenly acquired by P. aeruginosa, permitting its sterilization (>99.99%) by irradiation with near-infrared (NIR) light, irrespective of antibiotic resistance. Our findings substantiate that bacterial heme uptake via protein–protein recognition is an attractive target for antimicrobials, enabling specific and effective sterilization.