Polycationic phosphorous dendrimer potentiates multiple antibiotics against drug-resistant mycobacterial pathogens.

Mycobacterium tuberculosis (Mtb), causative agent of tuberculosis (TB) and non-tubercular mycobacterial (NTM) pathogens such as Mycobacterium abscessus are one of the most critical concerns worldwide due to increased drug-resistance resulting in increased morbidity and mortality. Therefore, focusing on developing novel therapeutics to minimize the treatment period and reducing the burden of drug-resistant Mtb and NTM infections are an urgent and pressing need. In our previous study, we identified anti-mycobacterial activity of orally bioavailable, non-cytotoxic, polycationic phosphorus dendrimer 2G0 against Mtb. In this study, we report ability of 2G0 to potentiate activity of multiple classes of antibiotics against drug-resistant mycobacterial strains. The observed synergy was confirmed using time-kill kinetics and revealed significantly potent activity of the combinations as compared to individual drugs alone. More importantly, no re-growth was observed in any tested combination. The identified combinations were further confirmed in intra-cellular killing assay as well as murine model of NTM infection, where 2G0 potentiated the activity of all tested antibiotics significantly better than individual drugs. Taken together, this nanoparticle with intrinsic antimycobacterial properties has the potential to represents an alternate drug candidate and/or a novel delivery agent for antibiotics of choice for enhancing the treatment of drug-resistant mycobacterial pathogens.

EphH, a unique epoxide hydrolase encoded by Rv3338 is involved in the survival of Mycobacterium tuberculosis under in vitro stress and vacuolar pH-induced changes.

Introduction: Mycobacterium tuberculosis (Mtb), one of the deadliest human pathogen, has evolved with different strategies of survival inside the host, leading to a chronic state of infection. Phagosomally residing Mtb encounters a variety of stresses, including increasing acidic pH. To better understand the host-pathogen interaction, it is imperative to identify the role of various genes involved in the survivability of Mtb during acidic pH environment. Methods: Bio-informatic and enzymatic analysis were used to identify Mtb gene, Rv3338, as epoxide hydrolase. Subsequently, CRISPRi knockdown strategy was used to decipher its role for Mtb survival during acidic stress, nutrient starvation and inside macrophages. Confocal microscopy was used to analyse its role in subverting phagosomal acidification within macrophage. Results: The present work describes the characterization of Rv3338 which was previously known to be associated with the aprABC locus induced while encountering acidic stress within the macrophage. Bio-informatic analysis demonstrated its similarity to epoxide hydrolase, which was confirmed by enzymatic assays, thus, renamed EphH. Subsequently, we have deciphered its indispensable role for Mtb in protection from acidic stress by using the CRISPRi knockdown strategy. Our data demonstrated the pH dependent role of EphH for the survival of Mtb during nutrient starvation and in conferring resistance against elevated endogenous ROS levels during stress environment. Conclusion: To the best of our knowledge, this is the first report of an EH of Mtb as a crucial protein for bacterial fitness inside the host, a phenomenon central to its pathogenesis.

The CODYSUN Approach: A Novel Distributed Paradigm for Dynamic Spectrum Sharing in Satellite Communications.

With a constant increase in the number of deployed satellites, it is expected that the current fixed spectrum allocation in satellite communications (SATCOM) will migrate towards more dynamic and flexible spectrum sharing rules. This migration is accelerated due to the introduction of new terrestrial services in bands used by satellite services. Therefore, it is important to design dynamic spectrum sharing (DSS) solutions that can maximize spectrum utilization and support coexistence between a high number of satellite and terrestrial networks operating in the same spectrum bands. Several DSS solutions for SATCOM exist, however, they are mainly centralized solutions and might lead to scalability issues with increasing satellite density. This paper describes two distributed DSS techniques for efficient spectrum sharing across multiple satellite systems (geostationary and non-geostationary satellites with earth stations in motion) and terrestrial networks, with a focus on increasing spectrum utilization and minimizing the impact of interference between satellite and terrestrial segments. Two relevant SATCOM use cases have been selected for dynamic spectrum sharing: the opportunistic sharing of satellite and terrestrial systems in (i) downlink Ka-band and (ii) uplink Ka-band. For the two selected use cases, the performance of proposed DSS techniques has been analyzed and compared to static spectrum allocation. Notable performance gains have been obtained.