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There is an urgent global need for new strategies and drugs to control and treat multi-drug resistant bacterial infections. In 2017, the World Health Organization (WHO) released a list of 12 antibiotic-resistant priority pathogens and began to critically analyze the antibacterial clinical pipeline. This review analyzes ‘traditional’ and ‘non-traditional’ antibacterial agents and modulators in clinical development current on 30 June 2021 with activity against the WHO priority pathogens, mycobacteria and Clostridioides difficile. Since 2017, 12 new antibacterial drugs have been approved globally, but only vaborbactam belongs to a new antibacterial class. Also innovative is the cephalosporin derivative cefiderocol, which incorporates an iron-chelating siderophore that facilitates Gram-negative bacteria cell entry. Overall, there were 76 antibacterial agents in clinical development (45 traditional and 31 non-traditional) with 28 in Phase 1, 32 in Phase 2, 12 in Phase 3 and four under regulatory evaluation. Forty-one out of 76 (54%) targeted WHO priority pathogens, 16 (21%) against mycobacteria, 15 (20%) against C. difficile and 4 (5%) are non-traditional agents with broad spectrum effects. Nineteen of the 76 antibacterial agents have new pharmacophores and four of these have new modes of actions not previously exploited by marketed antibacterial drugs. Despite there being 76 antibacterial clinical candidates, this analysis indicated that there were still relatively few clinically differentiated antibacterial agents in late-stage clinical development, especially against critical Priority Pathogens. We believe that future antibacterial R&D should focus on the development of innovative and clinically differentiated candidates that have clear and feasible progression pathways to the market.

The WHO launched a Global Action Plan on antimicrobial resistance (AMR) in 2015. World leaders in the G7, G20 and the UN General Assembly have declared AMR to be a global crisis. World leaders have also adopted universal health coverage (UHC) as a key target under the sustainable development goals. This paper argues that neither initiative is likely to succeed in isolation from the other and that the policy goals should be to both provide access to appropriate antimicrobial treatment and reduce the risk of the emergence and spread of resistance by taking a systems approach. It focuses on outpatient treatment of human infections and identifies a number of interventions that would be needed to achieve these policy goals. It then shows how a strategy for achieving key attributes of a health system for UHC can take into account the need to address AMR as part of a UHC strategy in any country. It concludes with a list of recommended priority actions for integrating initiatives on AMR and UHC.

Surfactant-mediated removal of proteins from biomembranes invariably results in partial or complete loss of function and disassembly of multi-protein complexes. We determined the capacity of styrene-co-maleic acid (SMA) co-polymer to remove components of the cell division machinery from the membrane of drug-resistant staphylococcal cells. SMA-lipid nanoparticles solubilized FtsZ-PBP2-PBP2a complexes from intact cells, demonstrating the close physical proximity of these proteins within the lipid bilayer. Exposure of bacteria to (-)-epicatechin gallate, a polyphenolic agent that abolishes β-lactam resistance in staphylococci, disrupted the association between PBP2 and PBP2a. Thus, SMA purification provides a means to remove native integral membrane protein assemblages with minimal physical disruption and shows promise as a tool for the interrogation of molecular aspects of bacterial membrane protein structure and function.

Despite ongoing efforts to stimulate investment and research into the development of new antibiotics, the clinical pipeline remains insufficient, in particular to treat critical resistant Gram-negative bacterial infections. The two new reports released by the World Health Organization on the preclinical and clinical antibacterial pipeline show that the current clinical pipeline is very dry and dominated by derivatives of existing classes. There are only 32 antibacterials in the clinical pipeline that target the WHO priority pathogens, of which only 6 fulfill at least 1 of the innovation criteria as defined by the WHO. Further upstream, the preclinical pipeline review identified 252 antibacterial agents in preclinical development of which over one third are nontraditioanl products which highlights the degree of innovation in the preclinical pipeline. The pipeline is also heavily reliant on small- or medium-sized enterprises, which is unsustainable in the long run, and more investment, more players, and a rethinking of the market dynamics is needed. It is encouraging that the pharmaceutical industry, governments, and other concerned stakeholders are currently discussing new ideas.

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We examined the impact of gradual removal of hydroxyl groups from the A-and B-rings of ( -)-epicatechin gallate on antibacterial activity and oxacillin resistance attenuation of an epidemic strain of methicillin resistant Staphylococcus aureus. Removal of both hydroxyls from the B-ring effected a large reduction in oxacillin MIC (from 512 to 0.25 mg/mL at a concentration of 12.5 mg/L); further hydroxyl deletion of the A-ring reduced the oxacillin effect but increased intrinsic anti-staphylococcal activity Keywords MRSA; ( -)-Epicatechin gallate analogues; β-Lactam antibiotics; Antibacterial chemotherapy; Antibiotic resistanceExtracts of the tea plant, Camellia sinensis, contain abundant quantities of both galloyl and nongalloyl catechins; these polyphenols constitute around 20% of the dry leaf weight and contribute to the weak antibacterial activity of green tea preparations. 1 Subinhibitory concentrations of these secondary metabolites exert a range of effects on bacterial cells that have the potential to be harnessed for therapeutic and industrial use. For example, moderate concentrations of ( -)-epicatechin gallate (ECg), and to a lesser extent ( -)-epigallocatechin gallate (EGCg) and ( -)-catechin gallate (Cg), disrupt the β-lactam-resistance machinery of methicillin resistant strains of Staphylococcus aureus (MRSA), inducing complete but reversible susceptibility to this important group of antibiotics. 2 Galloyl catechins also inhibit formation of staphylococcal biofilms, 3,4 reduce the secretion of toxins and other virulencerelated proteins by S. aureus strains 5 and abolish halotolerance in staphylococcal strains associated with food spoilage and food poisoning. 6 Although the processes involved in these phenotypic modifications are as yet incompletely defined, there is strong evidence that they are dependent on the intercalation of the bioactive polyphenols into the bacterial cytoplasmic membrane (CM): the most potent modifier, ECg (Fig. 1), inserts into the staphylococcal bilayer, inducing a series of complex changes to the phospholipid palisade and leading to reduction in the efficiency of function of CM-embedded proteins such as the penicillin binding proteins responsible for peptidoglycan biosynthesis and β-lactam resistance. 4 on the basis of enhanced microbiological activity of ECg, that a further reduction in the degree of B-ring hydroxylation would enhance anti-MRSA effects by increasing the affinity of these analogues for lipid bilayers. In addition B-ring 4-hydroxyl deletion should also give compounds less prone to epimerization via a quinone methide-like intermediate due to the removal of this anchimeric assistance. 10 We demonstrated that a monohydroxylated 3-hydroxy B-ring 1 and a dihydroxylated 3,5-dihydroxy B-ring 2 ECg analogue sensitised MRSA strains to the β-lactam antibiotic oxacillin to a comparable extent compared to the natural product (Fig. 1). 10 In combination with hydrolytically more stable analogues possessing an amide linked gallate group 3, 11 these modifications may ...