β-lactam antibiotics are one of the most widely used and diverse classes of antimicrobial agents for treating both Gram-negative and Gram-positive bacterial infections. The β-lactam antibiotics, which include penicillins, cephalosporins, monobactams and carbapenems, exert their antibacterial activity by inhibiting the bacterial cell wall synthesis and have a global positive impact in treating serious bacterial infections. Today, β-lactam antibiotics are the most frequently prescribed antimicrobial across the globe. However, due to the widespread use and misapplication of β-lactam antibiotics in fields such as human medicine and animal agriculture, resistance to this superlative drug class has emerged in the majority of clinically important bacterial pathogens. This heightened antibiotic resistance prompted researchers to explore novel strategies to restore the activity of β-lactam antibiotics, which led to the discovery of β-lactamase inhibitors (BLIs) and other β-lactam potentiators. Although there are several successful β-lactam-β-lactamase inhibitor combinations in use, the emergence of novel resistance mechanisms and variants of β-lactamases have put the quest of new β-lactam potentiators beyond precedence. This review summarizes the success stories of β-lactamase inhibitors in use, prospective β-lactam potentiators in various phases of clinical trials and the different strategies used to identify novel β-lactam potentiators. Furthermore, this review discusses the various challenges in taking these β-lactam potentiators from bench to bedside and expounds other mechanisms that could be investigated to reduce the global antimicrobial resistance (AMR) burden.

The deflection of cosmic rays (CRs) in the interstellar magnetic field results in an almost isotropic flux as observed on Earth. However, an anisotropy has been observed at the level of ∼ 10 −4 − 10 −3 . The GRAPES-3 experiment located at Ooty, India consists of an array of 400 plastic scintillator detectors. It measures the particle densities and their relative arrival times in extensive air showers produced by the CRs. This information collected is then reconstructed to obtain the energy and direction of the primary CRs. The near-equatorial location of GRAPES-3 provides an opportunity to study this anisotropy in both hemispheres of the celestial sphere in the TeV-PeV energy range. However, detector and atmospheric effects that induce a few percent change in the primary CR flux are challenges to be addressed. This work describes the use of time scrambling method to address some these systematics and observe anisotropy.

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High-resolution two-dimensional map of the solar time anisotropy obtained by the GRAPES-3 large-area muon telescope

Cosmic ray (CR) anisotropy of several scales have been observed over the last decade by a number of experiments located in the Northern and Southern hemispheres. The GRAPES-3 experiment, located at 11.4 • N can observe a significant portion of both the hemispheres and covers about 56% of the sky at TeV energies. Several small-scale anisotropic features, with a strength of ∼ 10 −4 − 10 −3 , have been observed using four years of GRAPES-3 data collected within a period of 2013-2016, by using the method of time-scrambling. Two striking hot-spot regions have been observed with a significance of more than 4𝜎. These structures are consistent with the observations reported by Milagro, ARGO-YBJ and HAWC. These structures, their characteristic features and a comparison of results from other experiments are described in this work.