Pyrazinamide (PZA) is a first-line tuberculosis drug that plays a unique role in shortening the duration of tuberculosis chemotherapy. PZA is hydrolyzed intracellularly to pyrazinoic acid (POA) by pyrazinamidase (PZase), an enzyme frequently lost in PZA-resistant strains, but the downstream target of POA in Mycobacterium tuberculosis (Mtb) has remained elusive. Here we identify a new target of POA as the ribosomal protein S1 (RpsA), a vital protein involved in protein translation and the ribosome-sparing process of trans-translation. Affinity chromatography using immobilized POA selectively retained RpsA and a PZA-resistant clinical isolate without pncA mutation harbored an alanine deletion in its C-terminus. RpsA overexpression conferred increased PZA resistance and we confirmed biochemically that POA bound to RpsA (but not the ΔAla mutant) and inhibited trans-translation rather than canonical translation. Trans-translation is essential for freeing scarce ribosomes in non-replicating organisms and its inhibition may explain the unique ability of PZA to eradicate persisting organisms.

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Abstract. This paper concerns transonic shocks in compressible inviscid flow passing a twodimensional variable-area duct for the complete steady Euler system. The flow is supersonic at the entrance of the duct, whose boundaries are slightly curved. The condition of impenetrability is posed on the boundaries. After crossing a nearly flat shock front, which passes through a fixed point on the boundary of the duct, the flow becomes subsonic. We show that to ensure the stability of such shocks, pressure should not be completely given at the exit: it only should be given with freedom one, that is, containing an unknown constant to be determined by the upstream flow and the profile of the duct. Careful analysis shows that this is due to the requirement of conservation of mass in the duct. We used Lagrangian transformation and characteristic decomposition to write the Euler system as a 2 × 2 system, which is valid for general smooth flows. Due to such a simplification, we can employ the theory of boundary value problems for elliptic equations to discuss well-posedness or ill-posedness of transonic shock problems in variable-area duct for various conditions giving at the exit.

We establish the stability of a class of cylindrical symmetric transonic shocks for two-dimensional complete compressible steady Euler system. This result partly explains the effectiveness of the popular quasi-one-dimensional model of nozzle flows used in aerodynamics. Mathematically, we solve a nonlinear free boundary problem of an elliptic-hyperbolic composite system, with the circular transonic shock front as the free boundary. We accomplish this by finding a (locally) unique fixed point of an appropriately defined boundary profile updating mapping. To define this mapping, we encounter a series of nonclassical boundary value problems in an annulus, which involve a new type of nonlocal elliptic problem, and integral-like solvability conditions to determine the position of the free boundary. This reflects an interesting new feature of boundary value problems of elliptic-hyperbolic composite systems.