Cephalosporin-NO-donor prodrug PYRRO-C3D shows β-lactam-mediated activity against Streptococcus pneumoniae biofilms

Bacterial biofilms show high tolerance towards antibiotics and are a significant problem in clinical settings where they are a primary cause of chronic infections. Novel therapeutic strategies are needed to improve anti-biofilm efficacy and support reduction in antibiotic use. Treatment with exogenous nitric oxide (NO) has been shown to modulate bacterial signaling and metabolic processes that render biofilms more susceptible to antibiotics. We previously reported on cephalosporin-3\u27-diazeniumdiolates (C3Ds) as NO-donor prodrugs designed to selectively deliver NO to bacterial infection sites following reaction with β-lactamases. With structures based on cephalosporins, C3Ds could, in principal, also be triggered to release NO following β-lactam cleavage mediated by transpeptidases/penicillin-binding proteins (PBPs), the antibacterial target of cephalosporin antibiotics. Transpeptidase-reactive C3Ds could potentially show both NO-mediated anti-biofilm properties and intrinsic (β-lactam-mediated) antibacterial effects. This dual-activity concept was explored using Streptococcus pneumoniae, a species that lacks β-lactamases but relies on transpeptidases for cell-wall synthesis. Treatment with PYRRO-C3D (a representative C3D containing the diazeniumdiolate NO donor PYRRO-NO) was found to significantly reduce viability of planktonic and biofilm pneumococci, demonstrating that C3Ds can elicit direct, cephalosporin-like antibacterial activity in the absence of β-lactamases. While NO release from PYRRO-C3D in the presence of pneumococci was confirmed, the anti-pneumococcal action of the compound was shown to arise exclusively from the β-lactam component and not through NO-mediated effects. The compound showed similar potency to amoxicillin against S. pneumoniae biofilms and greater efficacy than azithromycin, highlighting the potential of C3Ds as new agents for treating pneumococcal infections

Mg2+-dependent conformational equilibria in CorA and an integrated view on transport regulation

The CorA family of proteins regulates the homeostasis of divalent metal ions in many bacteria, archaea, and eukaryotic mitochondria, making it an important target in the investigation of the mechanisms of transport and its functional regulation. Although numerous structures of open and closed channels are now available for the CorA family, the mechanism of the transport regulation remains elusive. Here, we investigated the conformational distribution and associated dynamic behaviour of the pentameric Mg2+ channel CorA at room temperature using small-angle neutron scattering (SANS) in combination with molecular dynamics (MD) simulations and solid-state nuclear magnetic resonance spectroscopy (NMR). We find that neither the Mg2+-bound closed structure nor the Mg2+-free open forms are sufficient to explain the average conformation of CorA. Our data support the presence of conformational equilibria between multiple states, and we further find a variation in the behaviour of the backbone dynamics with and without Mg2+. We propose that CorA must be in a dynamic equilibrium between different non-conducting states, both symmetric and asymmetric, regardless of bound Mg2+ but that conducting states become more populated in Mg2+-free conditions. These properties are regulated by backbone dynamics and are key to understanding the functional regulation of CorA.Peer reviewe

The design and synthesis of novel anti-malarial agents

A new convergent methodology has been developed for the synthesis of the anti-malarial lead compound ADAM (24). A series of 41 derivatives were successfully synthesized, 35 of which were new compounds; all of which related to ADAM (24). All the synthesized derivatives were screened against in vitro Plasmodium falciparum K1, of which 11 showed significant activity in the low micromolar range, including compound (46) (IC50 0.3 ?g/ml), (80) (0.7 ?g/ml). and (88) (1.4 ?g/ml). A preliminary structure activity relationship analysis study was performed, which suggested that while 4,6-diaminopyrimidine analogs are inactive, if one of the two amines are alkylated then anti-malarial activity is returned. In order to generate a more thorough analysis, more compounds need to be synthesized by modifying the side chain. The SAR study also suggests that the heteroatom nitrogens in the pyrimidine ring are required for anti-malarial activity. The entire range of derivatives based on 5-benzoyl-4,6-dichloropyrimidine are inactive. The replacement of the phenyl substituent with an isopropyl group resulted in good anti-malarial activity but less than the parent compound. Novel synthetic dimerising methodology mediated by thallium(III) trifluoroacetate has been developed for the synthesis of biindoles. The methodology included the development of 2,2- and 2,7-biindoles, and 2,7,7,7-triindole. A series of 41 new indole derivatives were synthesized and screened for anti-malarial activity, of which three showed significant anti-malarial activity. During this study, the dimerisation of indole mediated by triflic anhydride was demonstrated for the first time. There are two other interesting synthetic results were observed, the triflic anhydride-mediated bi-pyrroloindole formation and the formation of the 1,2-dihydropyridineindole. Most compounds synthesized here were further tested in a series of additional biological assays, and a number of them showed activity against HIV reverse transcriptase, integrase, tuberculosis, anti-fungal and anti-cancer. In particular, the biaryl derivatives showed moderate activity against tuberculosis and fungal, which may be able to investigate further. A couple of biaryl compounds also showed significant anti-cancer activity. [Note: this abstract contained scientific formulae that would not come across on this form. Please see the 01Front files abstract for the full details.

Wireless energy harvesting based relaying : a diversity multiplexing tradeoff perspective

This thesis presents a radio frequency (RF)-based energy harvesting (EH) coupled with relaying-based communication as a solution to address the end-to-end quality-of-service (QoS) requirements of future wireless communication systems. Typically, an increase in data rate leads to a rise in error probability. Conversely, to improve reliability, the system must sacrifice the achievable data rate. Thus, there is an inherent tradeoff between these two metrics. For quasi-static fading channels, Zheng and Tse proposed a fundamental performance metric, diversity-multiplexing tradeoff (DMT), to formalize the relationship between rate and reliability at asymptotically high signal-to-noise ratios. A direct characterization of the DMT for RF-EH-based relay channels is in general difficult because the transmission power of RF-EH-based relay is a function of source-to-relay channel gain. In this thesis, the DMT framework has been adapted to suit this class of channels. The essence of this work is in deriving the closed-form expressions for the DMT in the high-SNR regime. Specifically, the focus is on the time-switching- based scheme in which the intermediate relay switches between energy harvesting (EH), information decoding (ID), and the information retransmission (IR). In the single-relay case, the DMT has been characterized for dynamic decode-and- forward (DDF) and non-orthogonal amplify-and-forward (NAF) protocols. An investigation of these RF-EH-based protocols yields a detailed characterization of the limitations of energy harvesting concerning optimal performance. In particular, an interesting conceptual relation between the diversity gain and the energy- harvesting interval has been found. It is observed that the achievable diversity gain improves with the reduction in energy-harvesting interval. Moreover, a comparison with various benchmarking schemes has established the supremacy of RF-EH-based DDF among all the proposed relaying protocols. Next, a multiple-access relay system (MARS), where the relay node powered by RF-EH, is analyzed. For this system, the DMT is characterized for two variants of EH-based DDF protocols: without feedback (EH-DDF) and with limited feedback (EH-DDF-LF). Analysis of these protocols reveals that the diversity gain of EH- DDF scheme is inferior to that of traditional non-EH-based DDF protocol. On the other hand, EH-DDF-LF achieves optimal diversity gain in the high-multiplexing- gain regime. Subsequently, the DMT study has been extended to an interference- limited relay-aided communication system in the moderate-interference regime. Unfortunately, the asymptotic (high-SNR) DMT does not reveal the tradeoff between diversity and multiplexing gains at low to moderate SNRs. Thus, there is a need to characterize the DMT for finite SNR regimes to assess the complete picture on the effects of various design parameters. In this work, an analytical framework to derive closed-form expressions for finite SNR DMT (f-DMT) for RF- EH-based amplify-and-forward (AF) and decode-and-forward (DF) protocols is also proposed. The results of this investigation suggest that the DF offers superior performance in the low-SNR regime, whereas AF performs better in high-SNR scenarios. Furthermore, an analytical study is presented to evaluate the effect of the fraction of time devoted to RF-EH (time-sharing parameter, E) on the f-DMT. For both AF and DF, it is shown that the optimum E depends on the operating SNR. However, it is observed that the influence of E is nominal in the high-SNR regime. As a result, it is concluded that the asymptotic DMT has its relevance, even though it hides a few finer details.Doctor of Philosoph

Optimal algorithms for energy harvesting based systems with circuit power considerations

Recently, an elegant method to alleviate the shortcomings of battery-powered (BP) sensor nodes has been introduced in the form of energy harvesting (EH), where the nodes scavenge the energy from ambient sources. Optimal scheduling algorithms, either to minimize transmission completion time or to maximize short-term throughput, for such networks under the deterministic energy and data arrival profiles are extensively studied in the literature. In this work, we revisited the existing optimal algorithms under practical energy cost considerations: circuit power consumption and sleep-to-wakeup power consumption. Next, we found that the direct application of the state-of-the-art algorithms led to sub-optimality. Finally, we proposed suitable adaptations to regain optimality.Accepted versio

On wireless energy harvesting based relaying for interference-limited user : a DMT perspective

In this paper, the diversity-multiplexing tradeoff (DMT) is investigated for an interference-limited relay-aided communication system in the moderate interference regime. Further, in the proposed system, the relay node is powered by wireless energy harvesting (WEH). In particular, this work studies the impact of energy harvest duration at the relay node on the achievable DMT of an interference-limited user using a variant of dynamic decode-and-forward based protocol. Our results show that the DMT of interference-limited user degrades with the proportional increase in energy harvest duration at low multiplexing gains. On the other hand, it is observed that the DMT of WEH-based interference-limited user approaches that of non-EH-based counterpart for higher multiplexing gains.Accepted versio

On the DMT of RF energy harvesting-based dynamic decode-and-forward relaying

A multiple relay-based system, where all the relay nodes powered by radio frequency-based energy harvesting (EH), is considered. The present letter characterizes the diversity-multiplexing tradeoff (DMT) for EH-based dynamic decode-and-forward (EH-DDF) protocol for independent quasi-static Rayleigh faded channels. It is shown that the achievable diversity gain of EH-DDF improves with the reduction in the EH intervals. However, it is observed that the performance difference exists between classical DDF and EH-DDF even for infinitesimal harvest duration in lower multiplexing gain region.Accepted versio

Wireless energy harvesting-based relaying : a finite-SNR diversity-multiplexing tradeoff perspective

This paper presents an analytical framework to derive the closed-form expressions for diversity-multiplexing tradeoff (DMT) for wireless energy harvesting (WEH) based amplify-and-forward (AF) and decode-and-forward (DF) protocols in finite signal-to-noise (SNR) regime. The results of this investigation suggest that both AF and DF offer similar performance except for few nuances. At low multiplexing gains, DF offers marginally better performance in the low SNR regime, whereas AF performs better in the high SNR scenarios. However, in the higher multiplexing gain regime, though subtle, DF uniformly dominates AF across all SNRs. Furthermore, an analytical study is presented to evaluate the effect of the fraction of time devoted to WEH (time-sharing parameter, ε) on the finite SNR DMT (f-DMT). In addition, the impact of relay position on the outage performance is also presented. A distinguishing feature of the proposed work is the characterization of WEH-based fDMT which reveals the complete interplay between the operating SNR and the time-sharing parameter (ε), which is of fundamental importance to system designers. Finally, Monte-Carlo simulations are provided to confirm the veracity of analytical solutions.Accepted versio

RF energy harvesting based multiple access relay systems : a DMT perspective

A multiple-access relay system, where the relay node is powered by radio frequency radiation is analyzed in this paper. Specifically, the focus is on the time-switching-based scheme in which the intermediate relay switches between the energy harvesting (EH), information decoding (ID), and the information re-transmission (TX). For this system, we have characterized the diversity-multiplexing trade-off (DMT) for two variants of the EH-based dynamic decode-and-forward (DDF) protocols: without feedback (EH-DDF) and with limited feedback (EH-DDF-LF). Analysis of the protocols reveals that the diversity gain of EHDDF scheme is inferior to that of the traditional non-EH-based DDF protocol. Furthermore, the impact of energy harvesting duration on the DMT performance has been extensively investigated. Consequently, it is observed that the achievable diversity gain of the EH-DDF improves with the reduction in energy harvesting interval. However, there exists a performance difference between the classical non-EH-based DDF and EHDDF even for the minute harvest duration. On the other hand, in the case of EH-DDF-LF, the performance approaches the diversity upper bound in the high multiplexing gain regime. Finally, a detailed comparison of the proposed EH-based schemes has been presented.Published versio