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

Abstract

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.

Permanent Photodynamic Activation of the Cholecystokinin 2 Receptor

“…Instead, the removal of central conjugated Zn 2+ rather drastically enhanced its dark antagonist activity [51]. Interestingly, in a separate report, it was found that a completely water-insoluble gallium-conjugated phthalocyanine without any peripheral substitutions (GaPc) could be bound and dissolved by the bacterial heme acquisition system (Has) protein A (HasA) transported via HasA receptors into Pseudomonas aeruginosa bacterial cells for subsequent photodynamic inactivation [52]. The recognition of SALPC by CCK2R, Zn-DIGP by CXCR3, and Ga-Pc by HasA all clearly indicate that phthalocyanines per se in the complete absence of light irradiation are an important class of bioeffective molecules.…”

Turning Photons into Drugs: Phthalocyanine‐Based Photosensitizers as Efficient Photoantimicrobials

“…Recently an interesting strategy was developed by Shisaka et al,w hereby the extracellular heme acquisition system protein A( HasA) wasu sed to accumulate water-insoluble GaPc into the intracellulars pace of P. aeruginosa via the protein recognition of HasA by the outer membrane receptor HasR (Figure 7b). [69] An irradiationt ime of only 10 min at al ight irradianceo f 10 mW cm À2 was sufficient to sterilizeo ver 99.99 %o fb acteria when 42 was used as PS. This strategy shows that water-soluble protein carriers may be able to successfully deliver PS to target bacteria.…”

“…by the outer membrane receptor HasR (Figure 7 b). [69] An irradiation time of only 10 min at a light irradiance of 10 mW cm −2 was sufficient to sterilize over 99.99 % of bacteria when 42 was used as PS. This strategy shows that water‐soluble protein carriers may be able to successfully deliver PS to target bacteria.…”

Tetraphenylporphyrin Enters the Ring: First Example of a Complex Between Highly Bulky Porphyrins and a Protein

“…1a), can accept various bulky synthetic metalloporphyrins, such as diphenylporphyrin. [34][35][36][37] Yet, at this time, we were unable to incorporate bulkier TPP into HasA and concluded that this may not be possible, 34,35 and that the TPP skeleton may be incompatible for incorporation into unadulterated proteins and application with natural biological systems.…”