Antimicrobial resistance (AMR) mediated by β-lactamases is the major and leading cause of resistance to penicillins and cephalosporins among Gram-negative bacteria. β-Lactamases, periplasmic enzymes that are widely distributed in the bacterial world, protect penicillin-binding proteins (PBPs), the major cell wall synthesizing enzymes, from inactivation by β-lactam antibiotics. Developing novel PBP inhibitors with a non-β-lactam scaffold could potentially evade this resistance mechanism. Based on the structural similarities between the evolutionary related serine β-lactamases and PBPs, we investigated whether the potent β-lactamase inhibitor, vaborbactam, could also form an acyl-enzyme complex with Pseudomonas aeruginosa PBP3. We found that this cyclic boronate, vaborbactam, inhibited PBP3 (IC50 of 262 μM), and its binding to PBP3 increased the protein thermal stability by about 2°C. Crystallographic analysis of the PBP3:vaborbactam complex reveals that vaborbactam forms a covalent bond with the catalytic S294. The amide moiety of vaborbactam hydrogen bonds with N351 and the backbone oxygen of T487. The carboxyl group of vaborbactam hydrogen bonds with T487, S485, and S349. The thiophene ring and cyclic boronate ring of vaborbactam form hydrophobic interactions, including with V333 and Y503. The active site of the vaborbactam-bound PBP3 harbors the often observed ligand-induced formation of the aromatic wall and hydrophobic bridge, yet the residues involved in this wall and bridge display much higher temperature factors compared to PBP3 structures bound to high-affinity β-lactams. These insights could form the basis for developing more potent novel cyclic boronate-based PBP inhibitors to inhibit these targets and overcome β-lactamases-mediated resistance mechanisms.

Sodium–glucose co-transporter inhibitors (SGLT2i) have recently gained a lot of emphasis in their role in preventing progression of chronic kidney disease and helping with cardiac mortality. Various studies have proven the benefit of these medications in the management of patients with kidney and heart disease. SGLT2i exert their effect in the proximal convoluted tubule with various downstream effects noted in the kidney also. With spreading use of these medications, it is imperative to understand the effects they have on various electrolytes and the pathways involved in bringing about these changes in the kidney. Here, the authors review the current knowledge of SGLT2i with their effects on the kidney, electrolytes, and water balance.

Diabetic kidney disease (DKD) has been an immense burden on the healthcare system, and is the leading cause of end stage kidney disease worldwide. DKD involves various intersecting pathways that lead to progressive kidney damage. Due to its versatile pathogenesis, DKD has been a formidable adversary. For many decades, there has not been much development in the arsenal in the fight against DKD, but recently, multiple new prospects have emerged due to the breakthrough in understanding of DKD pathology. Tireless research of the changes occurring in the kidney as a result of diabetes, and the factors driving these changes, has led to the invention of medications that hopefully will be highly impactful in preventing end stage kidney disease in patients with diabetes. In this review, the authors summarise the timeline of the pathological changes that occur in DKD, the mechanism driving these pathological changes, and the recent discoveries in the pathways leading to DKD. These span over changes in metabolic pathways, inflammatory cascades, epigenetic alterations, and the description of their effects at cellular to structural levels in the kidney as a byproduct of uncontrolled hyperglycaemia. The authors also correlate these mechanisms with a few of the medications that are being utilised to slow down DKD, and some in the pipeline, with some references to the trials that support their use.

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