Pathogenic microbes rapidly develop resistance to antibiotics. To keep ahead in the “microbial war”, extensive interdisciplinary research is needed. A primary cause of drug resistance is the overuse of antibiotics that can result in alteration of microbial permeability, alteration of drug target binding sites, induction of enzymes that destroy antibiotics (ie., beta-lactamase) and even induction of efflux mechanisms. A combination of chemical syntheses, microbiological and biochemical studies demonstrate that the known critical dependence of iron assimilation by microbes for growth and virulence can be exploited for the development of new approaches to antibiotic therapy. Iron recognition and active transport relies on the biosyntheses and use of microbe-selective iron-chelating compounds called siderophores. Our studies, and those of others, demonstrate that siderophores and analogs can be used for iron transport-mediated drug delivery (“Trojan Horse” antibiotics) and induction of iron limitation/starvation (Development of new agents to block iron assimilation). Recent extensions of the use of siderophores for the development of novel potent and selective anticancer agents are also described.

Mycobactins are a family of iron sequestering agents (siderophores) biosynthesized as growth promoters by mycobacteria including Mycobacterium tuberculosis. They are important siderophores with high affinity and specificity for Fe(III) due to the chemical nature of their component chelating functional groups. The parent compounds and their synthetic analogues can be used for studies of natural iron uptake mechanisms. It was hypothesized by Snow and co-workers that alternate and modified mycobactin analogues might serve as antagonists of mycobacterial growth and be of important therapeutic value. Efficient syntheses of four different analogues are presented. Dramatic improvements on formation of amide and ester bonds were achieved using water soluble carbodiimide (EDC‚HCl)-mediated couplings in the presence of 1-hydroxy-7-azabenzotriazole (HOAt) as an additive. Using HOAt over other traditional coupling additives provided significant enhancement of the reaction rate of the desired coupling reactions and minimized side reactions. Further simplifications were made possible by minimizing the use of protecting groups during the syntheses. In fact, coupling components in the presence of free hydroxamic acids and a free phenolic hydroxyl group proceeded in excellent yields. Biological studies indicated that the resulting synthetic analogues effect moderate to high inhibition of the growth of M. tuberculosis H37Rv.(1) Brown, D. U.S. Tuberculosis Cases Decline as Disease Increases Worldwide.

Mycobacterium tuberculosis survival in cells requires mycobactin siderophores. Recently, the search for lipid antigens presented by the CD1a antigen-presenting protein led to the discovery of a mycobactin-like compound, dideoxymycobactin (DDM). Here we synthesize DDMs using solution phase and solid phase peptide synthesis chemistry. Comparison of synthetic standards to natural mycobacterial mycobactins by nuclear magnetic resonance and mass spectrometry allowed identification of an unexpected ␣-methyl serine unit in natural DDM. This finding further distinguishes these pre-siderophores as foreign compounds distinct from conventional peptides, and we provide evidence that this chemical variation influences the T cell response. One synthetic DDM recapitulated natural structures and potently stimulated T cells, making it suitable for patient studies of CD1a in infectious disease. DDM analogs differing in the stereochemistry of their butyrate or oxazoline moieties were not recognized by human T cells. Therefore, we conclude that T cells show precise specificity for both arms of the peptide, which are predicted to lie at the CD1a-T cell receptor interface.

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For the first time, an experiment has been conducted to investigate synthetic jet laminar vortex rings impinging onto porous walls with different geometries by time-resolved particle image velocimetry. The geometry of the porous wall is changed by varying the hole diameter on the wall (from 1.0 mm to 3.0 mm) when surface porosity is kept constant ($\unicode[STIX]{x1D719}=75\,\%$). The finite-time Lyapunov exponent and phase-averaged vorticity field derived from particle image velocimetry data are presented to reveal the evolution of the vortical structures. A mechanism associated with vorticity cancellation is proposed to explain the formation of downstream transmitted vortex rings; and both the vortex ring trajectory and the time-mean flow feature are compared between different cases. It is found that the hole diameter significantly influences the evolution of the flow structures on both the upstream and downstream sides of the porous wall. In particular, for a porous wall with a small hole diameter ($d_{h}^{\ast }=0.067$, 0.10 and 0.133), the transmitted finger-type jets will reorganize into a well-formed transmitted vortex ring in the downstream flow. However, for the case of a large hole diameter of $d_{h}^{\ast }=0.20$, the transmitted vortex ring is not well formed because of insufficient vorticity cancellation. Additionally, the residual vorticity gradually evolves into discrete jet-like structures downstream, which further weaken the intensity of the transmitted vortex ring. Consequently, the transmitted flow structures for the $d_{h}^{\ast }=0.20$ case would lose coherence more easily (or probably even transition to turbulence), resulting in a faster decay of the axial velocity and stronger entrainment of the transmitted jet. For all porous wall cases, the velocity profile of the transmitted jet exhibits self-similar behaviour in the far field ($z/D_{0}\geqslant 6.03$), which agrees well with the velocity distribution of free synthetic jets. With the help of the control-volume approach, the time-mean drag of the porous wall is evaluated experimentally for the first time. It is shown that the porous wall drag increases with the decrease in the hole diameter. Moreover, for a porous wall with a small hole diameter ($d_{h}^{\ast }=0.067$, 0.10 and 0.133), it appears that the porous wall drag mainly derives from the viscous effect. However, as $d_{h}^{\ast }$ increases to 0.20, the form drag associated with the porous wall geometry becomes significant.

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