Identification of an ABC Transporter Required for Iron Acquisition and Virulence inMycobacterium tuberculosis

Abstract

Iron availability affects the course of tuberculosis infection, and the ability to acquire this metal is known to be essential for replication of Mycobacterium tuberculosis in human macrophages. M. tuberculosis overcomes iron deficiency by producing siderophores. The relevance of siderophore synthesis for iron acquisition by M. tuberculosis has been demonstrated, but the molecules involved in iron uptake are currently unknown. We have identified two genes (irtA and irtB) encoding an ABC transporter similar to the YbtPQ system involved in iron transport in Yersinia pestis. Inactivation of the irtAB system decreases the ability of M. tuberculosis to survive iron-deficient conditions. IrtA and -B do not participate in siderophore synthesis or secretion but are required for efficient utilization of iron from Fe-carboxymycobactin, as well as replication of M. tuberculosis in human macrophages and in mouse lungs. We postulate that IrtAB is a transporter of Fe-carboxymycobactin. The irtAB genes are located in a chromosomal region previously shown to contain genes regulated by iron and the major iron regulator IdeR. Taken together, our results and previous observations made by other groups regarding two other genes in this region indicate that this gene cluster is dedicated to siderophore synthesis and transport in M. tuberculosis.

Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling

“…5). The ATP-binding cassette iron-regulated transporter IrtAB is involved in the uptake of cMBT across the inner membrane (29). Furthermore, as the N-terminal domain of IrtA binds flavin adenine dinucleotide (30), it was suggested that the iron in Fe-cMBT is reduced, as it is imported into the cytoplasm.…”

“…and cMBT (Fe-cMBT) are acquired by Mtb by a process dependent on the ESX-3 secretion system (18, 47) (omitted for clarity) likely involving a siderophore receptor. Iron is dissociated from cMBT by IrtAB concomitant with its import (29,30). Iron is dissociated from MBT by a reductive process (31) at a yet-to-be-determined subcellular location.…”

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

“…Interessantemente, foi demonstrado que a ausência do gene IrtAB reduziu o processo de infecção pelo MTB. 97 Outro alvo potencial envolvido na obtenção de ferro inclui o EsX-3 e o sistema de sideróforos mmpS4/S5. 98 No entanto, não somente a obtenção como também o estoque de ferro é crucial para a sobrevivência do MTB.…”

Microbial Copper-binding Siderophores at the Host-Pathogen Interface

“…Transport through the Gram-negative outer membrane transporters occurs through specialized proteins associated with the TonB protein complex, which transduces energy from the cytoplasmic proton motive force (3,10,11). Inner membrane ATP-binding cassette transporters in both Gram-negative and Gram-positive organisms transport ferric siderophore complexes, or the iron released from them, to the cytoplasm (12)(13)(14)(15)(16). Once ferric siderophores are internalized, their intracellular fate varies between different siderophores, with reported examples of Fe(III) reduction to Fe(II) or Fe(III)-siderophore hydrolysis.…”

“…Once ferric siderophores are internalized, their intracellular fate varies between different siderophores, with reported examples of Fe(III) reduction to Fe(II) or Fe(III)-siderophore hydrolysis. All or part of the siderophore may be recycled and used again after releasing its metal ion cargo (2, 18).Although pathogens often carry multiple iron acquisition systems that are redundant in laboratory culture conditions, siderophore-dependent systems appear to play specialized roles at the host-pathogen interface (2,16,19,20). Specifically, siderophores have been ascribed roles in liberating ferric ions bound to host iron storage proteins or sequestered away from pathogens within distinctive compartments.…”