Essential Metabolic Routes as a Way to ESKAPE From Antibiotic Resistance

Abstract

Antibiotic resistance is a worldwide concern that requires a concerted action from physicians, patients, governmental agencies, and academia to prevent infections and the spread of resistance, track resistant bacteria, improve the use of current antibiotics, and develop new antibiotics. Despite the efforts spent so far, the current antibiotics in the market are restricted to only five general targets/pathways highlighting the need for basic research focusing on the discovery and evaluation of new potential targets. Here we interrogate two biosynthetic pathways as potentially druggable pathways in bacteria. The biosynthesis pathway for thiamine (vitamin B1), absent in humans, but found in many bacteria, including organisms in the group of the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter sp.) and the biosynthesis pathway for pyridoxal 5 ′ -phosphate and its vitamers (vitamin B6), found in S. aureus.Using current genomic data, we discuss the possibilities of inhibition of enzymes in the pathway and review the current state of the art in the scientific literature.

Transplant trends in Mexico during the COVID-19 pandemic: Disparities within healthcare sectors

“…In the first months, there was a shortage of personal protective equipment and poor working conditions leading to a high rate of SARS‐CoV‐2 infections, the highest rate among healthcare workers in the world. 14 In June 2020, they represented 21% of all individuals with laboratory‐confirmed SARS‐CoV‐2 infection, 15 and some institutions had to close due to COVID‐19 outbreaks. 14 Afterward, vulnerable personnel were removed, reducing the workforce in public institutions, and increasing the workload and psychological burden of the remaining personnel.…”

“… 14 In June 2020, they represented 21% of all individuals with laboratory‐confirmed SARS‐CoV‐2 infection, 15 and some institutions had to close due to COVID‐19 outbreaks. 14 Afterward, vulnerable personnel were removed, reducing the workforce in public institutions, and increasing the workload and psychological burden of the remaining personnel. 16 These factors limited the availability of healthcare workers for the care of transplant patients in the public setting.…”

Structural Dynamics and Perspectives of Vitamin B6 Biosynthesis Enzymes in Plasmodium: Advances and Open Questions

“…Wrenger and coworkers identified the genes for the enzymes Pdx1, Pdx2, and PdxK in Plasmodium falciparum , responsible for the biosynthesis and salvage of pyridoxal 5’-phosphate (PLP) ( Wrenger et al., 2005 ; Müller et al., 2010 ). In contrast to the biosynthesis pathway of thiamine, the de novo biosynthesis of PLP (vitamin B 6 ) requires only two enzymes (Pdx1 and Pdx2) to form a complex (Pdx1-Pdx2 or PLP synthase complex) ( Barra et al., 2020 ). The reaction catalyzed by the PLP synthase complex is shown in Supplementary Figure S1 , while the individual reactions catalyzed by Pdx1 and Pdx2 are shown in Figures 1A , 3A .…”

“…Therefore, selected drug targets should be distinctly different from the host’s metabolic processes, or even absent in the host ( Begum et al., 2013 ). In this context, the presence of the PLP synthesis enzymes in the metabolic pathways of the majority of organisms, including bacteria, fungi, protozoans, and plants, and their absence in humans ( Barra et al., 2020 ) avoids the off-target binding and potential side effects.…”

Engineered Cationic Antimicrobial Peptides (eCAPs) to Combat Multidrug-Resistant Bacteria

“…The development and the clinical use of the traditional classes of antibiotics, both prophylactically and therapeutically, have facilitated many of the advances in modern medicine. However, over the past three decades, the alarming rate of multidrug-resistance (MDR) has threatened to end the antibiotic era [ 1 , 2 ]. If this trend continues without increasingly effective countermeasures, it may become very difficult to perform many medical and surgical procedures that were challenging to perform prior to the commercialization of traditional antibiotics.…”