Current therapeutic options for human treponematoses, syphilis and yaws, are, broadly speaking, restricted to one antibiotic: injectable penicillin. The drug susceptibility profile of Treponema pallidum (T.p) is unknown because the microorganism could not be grown in culture. Treatment failure after penicillin has been related to syphilis bacteria that survive in the central nervous system (CNS) and the potential of strains to acquire resistance to penicillin has recently been recognized. Yaws can be treated with azithromycin but there is a real risk that macrolide-resistant strains disseminate widely and jeopardize the global eradication campaign. I propose a research program to have other validated treatment options with good CNS penetration that are efficacious for all the stages of treponemal infection. Our preliminary results using computational prediction of drug activity based on similarity to drugs with known activity against T.p. and other spirochetes shows several candidate antibiotics. I will take advantage of recent developments in culture methods for determination of drug susceptibility to test 20 prioritized drugs. These results will be confirmed in experimentally infected rabbits treated with the investigational drugs and assessed for lesion development and T.p. burden. My second approach will exploit the established expertise of my team conducting randomized clinical trials to evaluate the efficacy of the 2 most promising candidates compared to standard treatment to cure patients with syphilis/yaws. Such studies will incorporate in-depth studies of recurrent events among study participants, to further clarify the biological basis and identify mutations that confer resistance to B-lactams. New antibacterial oral drugs for the treatment of treponematoses will be a tremendous resource in case of penicillin treatment-failure, resistance, shortage, allergy, or for use in yaws combination regimens to reduce the likelihood of resistance selection.

Emergent particles with nonabelian exchange statistics are a key element in the understanding of topological condensed matter system. However, the nonabelian nature has never been demonstrated experimentally, nor has the intimately connected nonlocality of quantum states been observed in any physical system. With this proposal, we outline a research program whose goal is to design and carry out experiments, with close theoretical coupling, that can – for the first time – verify or falsify the existence of these fascinating novel degrees of freedom and then, if observed, quantify the spatial and temporal limits for the nonabelian and nonlocal properties. The platform for the research is based on topological superconductivity in hybrid materials, a field in which the applicants have played a leading role. We put together a team of experimental and theoretical physicists in a strongly collaborative setup. The focus of the proposal is Majorana bound states, which exist at the boundaries of topological superconductors. Experiments have over the past five years shown observations consistent with their existence. All these experiments are based on local probes which cannot reveal the inner nature of their nonlocal and nonabelian properties. To address the fundamental aspects of nonlocality, we will design quantum devices that combine topological superconductors with known condensed matter quantum technologies, including quantum dots, two-dimensional electron gases, and fast measurement techniques. The nonabelian nature will be explored by design of multi-Majorana devices and of protocols that can reveal the nonabelian nature of braids in the space of topologically-protected groundstate manifolds. The gained knowledge will provide a breakthrough in the fundamentals of emergent degrees of freedom and quantum states encoded in topological macroscopic systems. Their possibly profound character might have future applications in quantum technologies.