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Using artificial hemes for the reconstruction of natural heme proteins represents a fascinating approach to enhance the bioactivity of the latter. We report the synthesis of various metal 5-oxaporphyrinium cations as cofactors, and a cobalt 5-oxaporphyrinium cation was successfully incorporated into the heme-acquisition protein (HasA) secreted by Pseudomonas aeruginosa. We hypothesize that the oxaporphyrinium cation strongly binds to the HasA-specific outer membrane receptor (HasR) due to its cationic charge, which prevents the subsequent acquisition of heme. In fact, the reconstructed HasA inhibited the growth of Pseudomonas aeruginosa and even of multidrug-resistant P. aeruginosa., (© 2021 Wiley-VCH GmbH.)

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.

Iron(III)-5,15-diphenylporphyrin and several derivatives were accommodated by HasA, a heme acquisition protein secreted by Pseudomonas aeruginosa, despite possessing bulky substituents at the meso position of the porphyrin. Crystal structure analysis revealed that the two phenyl groups at the meso positions of porphyrin extend outside HasA. It was shown that the growth of P. aeruginosa was inhibited in the presence of HasA coordinating the synthetic porphyrins under iron-limiting conditions, and that the structure of the synthetic porphyrins greatly affects the inhibition efficiency., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The heme acquisition system A protein secreted by Pseudomonas aeruginosa (HasA(p)) can capture several synthetic metal complexes other than heme. The crystal structures of HasA(p) harboring synthetic metal complexes revealed only small perturbation of the overall HasA(p) structure. An inhibitory effect upon heme acquisition by HasA(p) bearing synthetic metal complexes was examined by monitoring the growth of Pseudomonas aeruginosa PAO1. HasA(p) bound to iron-phthalocyanine inhibits heme acquisition in the presence of heme-bound HasA(p) as an iron source., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Using artificial hemes for the reconstruction of natural heme proteins represents a fascinating approach to enhance the bioactivity of the latter. We report the synthesis of various metal 5‐oxaporphyrinium cations as cofactors, and a cobalt 5‐oxaporphyrinium cation was successfully incorporated into the heme‐acquisition protein (HasA) secreted by Pseudomonas aeruginosa. We hypothesize that the oxaporphyrinium cation strongly binds to the HasA‐specific outer membrane receptor (HasR) due to its cationic charge, which prevents the subsequent acquisition of heme. In fact, the reconstructed HasA inhibited the growth of Pseudomonas aeruginosa and even of multidrug‐resistant P. aeruginosa. [ABSTRACT FROM AUTHOR]

Iron(III)-5,15-diphenylporphyrin and several derivatives were accommodated by HasA, a heme acquisition protein secreted by Pseudomonas aeruginosa, despite possessing bulky substituents at the meso position of the porphyrin. Crystal structure analysis revealed that the two phenyl groups at the meso positions of porphyrin extend outside HasA. It was shown that the growth of P. aeruginosa was inhibited in the presence of HasA coordinating the synthetic porphyrins under iron-limiting conditions, and that the structure of the synthetic porphyrins greatly affects the inhibition efficiency. [ABSTRACT FROM AUTHOR]

[Display omitted] • The critical function of haem-acquisition system of gram-negative bacterial pathogens. • Artificial haem-acquisition protein HasAs harbouring synthetic metal complexes and their crystal structure analysis. • Antimicrobial applications of HasA capturing synthetic complexes. • Chemical applications of artificial-HasAs including catalytic utilities. Certain bacterial pathogens secrete haemophores, i.e. extracellular haem-uptake proteins, which acquire haem as a vital source of iron in the iron-devoid environment of their hosts. The haem-binding site of haemophores is highly exposed to the protein surface, enabling them to pirate haem from other haem-containing proteins (haemoproteins). This review will discuss the hidden ability of a representative haemophore, namely the haem-acquisition system protein A (HasA) secreted by Pseudomonas aeruginosa , which can accommodate a diverse assortment of synthetic metal complexes possessing extreme insolubility and/or high steric bulk in its haem-binding site. The replacement of haem with similar synthetic analogues is an already well established and powerful means to change the function of select haemoproteins; however, usable complexes are severely limited by the high selectivity of haemoproteins for haem. This review will introduce how combining the haem-replacement approach with HasA can open the door for the biological application of diverse synthetic metal complexes that were previously incompatible with biological systems. [ABSTRACT FROM AUTHOR]

The heme acquisition system A protein secreted by Pseudomonas aeruginosa (HasAp) can capture several synthetic metal complexes other than heme. The crystal structures of HasAp harboring synthetic metal complexes revealed only small perturbation of the overall HasAp structure. An inhibitory effect upon heme acquisition by HasAp bearing synthetic metal complexes was examined by monitoring the growth of Pseudomonas aeruginosa PAO1. HasAp bound to iron-phthalocyanine inhibits heme acquisition in the presence of heme-bound HasAp as an iron source. [ABSTRACT FROM AUTHOR]

Inside Back Cover: A Heme-Acquisition Protein Reconstructed with a Cobalt 5-Oxaporphyrinium Cation and Its Growth-Inhibition Activity Toward Multidrug-Resistant Pseudomonas aeruginosa (Angew. Cobalt, Heme, Multidrug-Resistant Pseudomonas Aeruginosa, Porphyrinoid, Reconstructed Protein Keywords: Cobalt; Heme; Multidrug-Resistant Pseudomonas Aeruginosa; Porphyrinoid; Reconstructed Protein EN Cobalt Heme Multidrug-Resistant Pseudomonas Aeruginosa Porphyrinoid Reconstructed Protein 1 1 1 02/03/22 20220207 NES 220207 B The purple cloud b (HasA; a heme acquisition protein) delivers cobalt oxaporphyrinium (orange porphyrin and red oxygen) to I Pseudomonas aeruginosa i (green). [Extracted from the article]

Keywords: Cobalt; Heme; Multidrug-Resistant Pseudomonas Aeruginosa; Porphyrinoid; Reconstructed Protein EN Cobalt Heme Multidrug-Resistant Pseudomonas Aeruginosa Porphyrinoid Reconstructed Protein 1 1 1 02/03/22 20220207 NES 220207 B Die violette Wolke b (HasA; ein Häm-Akquisitionsprotein) liefert Cobalt-Oxaporphyrinium (oranges Porphyrin und roter Sauerstoff) zu I Pseudomonas aeruginosa i (grün). Innenrücktitelbild: A Heme-Acquisition Protein Reconstructed with a Cobalt 5-Oxaporphyrinium Cation and Its Growth-Inhibition Activity Toward Multidrug-Resistant Pseudomonas aeruginosa (Angew. Cobalt, Heme, Multidrug-Resistant Pseudomonas Aeruginosa, Porphyrinoid, Reconstructed Protein. [Extracted from the article]