Antibiotic Pipeline Research Articles

Therapeutic Indices of Topical Antiseptics in Wound Care: A Systematic Review.

Chronic wounds place a heavy burden on healthcare systems and markedly reduce the ability of patients to engage in activities of daily living. One major factor contributing to impaired wound healing is bacterial bioburden. With the rise in antibiotic resistance and the slowdown in antibiotic development pipelines, alternative antimicrobial strategies are important. The objective of this systematic review is to determine the topical antiseptic therapeutic index values for bacterial species commonly isolated from chronic wounds. The therapeutic index is a ratio of the lowest concentration that causes mammalian cell cytotoxicity over the minimum bactericidal concentration. Higher values indicate greater safety and potential clinical benefit. A systematic literature search was performed in Medline and Embase, resulting in the inclusion of 37 articles that reported on the minimum bactericidal concentration in bacterial species commonly isolated from chronic wounds and their cytotoxicity concentrations in mammalian cells. The therapeutic indices for the topical antiseptics included in this study were generally low, with most ranging between 0.5-3.0. The highest therapeutic index values for Escherichia coli (5.49), Staphylococcus aureus (6.31) and Pseudomonas aeruginosa (8.81) were achieved by hypochlorous acid, whereas the highest therapeutic index values for methicillin resistant S aureus (12.1) was achieved by polyhexamethylenebiguanide. Antibiotic stewardship principles may need to be applied to topical antiseptics due to some isolated evidence of topical antiseptic resistance and cross-resistance to antibiotics. The choice of antiseptic should not be made solely based on therapeutic index values, but individualized to the patient, with consideration for the wound healing condition that may include covert infection.

Insights into small-molecule compound CY-158-11 antibacterial activity against Staphylococcus aureus.

The combination of the rising incidence of antibiotic resistance and the shrinking antibiotic pipeline has raised concern about the postantibiotic era. New antibacterial agents and targets are required to combat S. aureus-associated infections. In this study, we identified a maleimide-diselenide hybrid compound CY-158-11 exhibiting antibacterial activity against S. aureus in vitro and in vivo at relatively low concentrations. Furthermore, the investigation of its mode of action revealed that CY-158-11 can selectively perturb the cytoplasmic membrane of bacteria without harming mammalian cells or mouse organs. Thus, CY-158-11 is a compelling novel drug for development as a new therapy for S. aureus infections.

Semantic search using protein large language models detects class II microcins in bacterial genomes.

Antibiotic resistance is becoming an increasingly serious problem in modern medicine, but the development pipeline for conventional antibiotics is not promising. Therefore, alternative approaches to combat bacterial infections are urgently needed. One such approach may be to employ naturally occurring antibacterial peptides produced by bacteria to kill competing bacteria. A promising class of such peptides are class II microcins. However, only a small number of class II microcins have been discovered to date, and the discovery of further such microcins has been hampered by their high sequence divergence and short length, which can cause sequence-based search methods to fail. Here, we demonstrate that a more robust method for microcin discovery can be built on the basis of a protein large language model, and we use this method to identify several putative novel class II microcins.

Advancing global antibiotic research, development and access.

The pipeline of new antibiotics is insufficient to keep pace with the growing global burden of drug-resistant infections. Substantial economic challenges discourage private investment in antibiotic research and development (R&D), with a decline in the number of companies and researchers working in the field. Compounding these issues, many countries (from low income to high income) face a growing crisis of antibiotic shortages and inequitable access to existing and emerging treatments. This has led to an increasing role for public and philanthropic funding in supporting antibiotic R&D via the creation of nonprofit public-private partnerships, including Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) and the Global Antibiotic Research and Development Partnership (GARDP), industry support for the AMR Action Fund, and pilot schemes to evaluate and reimburse antibiotics in innovative ways. Now is the time to raise the urgency, ambition and commitments of the world's leaders to fully support the antibiotic R&D ecosystem, incentivizing all sectors to conduct public health-driven antibiotic R&D and make effective antibiotics accessible to all who need them.

The time to address the antibiotic pipeline and access crisis is now

The time to address the antibiotic pipeline and access crisis is now

The demise of the antibiotic pipeline: the Bayer case

Antibiotics, celebrated as symbols of scientific triumph and societal advancement, have played a critical role in combating infectious diseases. However, their overuse has inadvertently fueled the emergence of antibiotic resistance. The primary strategy to tackle the resistance has been to develop new antibiotics. However, since the 1980s, there has been a noticeable downturn in the development of new antibacterial drugs. This slump, often referred to as the ‘dry antibiotic pipeline’, was particularly prevalent during the 1990s and aligned with that; many major pharmaceutical companies exited the antibiotic field in the early 2000s. That is also the main timeframe this paper focuses on. This work analyzes the dry antibiotic pipeline as a historical phenomenon and sets the stage by outlining the narrative context and key actors involved. It then discusses critical elements such as the understanding of innovation, scientific advances, regulatory requirements for clinical trials, and commercial models. These elements were often considered factors explaining the difficulty of developing new antibiotics. Using the case of the pioneering German company Bayer, these elements are brought together to illustrate the complexity of the crisis in the research and development of antibiotics. The Bayer story provides new insights into the internal realities of the company and reveals a range of entangled and multilayered challenges, which ultimately resulted in Bayer abandoning its storied production of anti-infectives, particularly antibiotics, calling into question the common understanding of the dry antibiotic pipeline.

In vitro identification of underutilized β-lactam combinations against methicillin-resistant Staphylococcus aureus bacteremia isolates.

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is a serious clinical challenge with high mortality rates. Antibiotic combination therapy is currently used in cases of persistent infection; however, the limited development of new antibiotics will likely increase the need for combination therapy, and better methods are needed for identifying effective combinations for treating persistent bacteremia. To identify pairwise combinations with the most consistent potential for benefit compared to monotherapy with a primary anti-MRSA agent, we conducted a systematic study with an in vitro high-throughput methodology. We tested daptomycin and vancomycin each in combination with gentamicin, rifampicin, cefazolin, and oxacillin, and ceftaroline with daptomycin, gentamicin, and rifampicin. Combining cefazolin with daptomycin lowered the daptomycin concentration required to reach 95% growth inhibition (IC95) for all isolates tested and lowered daptomycin IC95 below the sensitivity breakpoint for five out of six isolates that had daptomycin minimum inhibitory concentrations at or above the sensitivity breakpoint. Similarly, vancomycin IC95s were decreased when vancomycin was combined with cefazolin for 86.7% of the isolates tested. This was a higher percentage than was achieved by adding any other secondary antibiotic to vancomycin. Adding rifampicin to daptomycin or vancomycin did not always reduce IC95s and failed to produce synergistic interaction in any of the isolates tested; the addition of rifampicin to ceftaroline was frequently synergistic and always lowered the amount of ceftaroline required to reach the IC95. These analyses rationalize further in vivo evaluation of three drug pairs for MRSA bacteremia: daptomycin+cefazolin, vancomycin+cefazolin, and ceftaroline+rifampicin.IMPORTANCEBloodstream infections caused by methicillin-resistant Staphylococcus aureus (MRSA) have a high mortality rate despite the availability of vancomycin, daptomycin, and newer antibiotics including ceftaroline. With the slow output of the antibiotic pipeline and the serious clinical challenge posed by persistent MRSA infections, better strategies for utilizing combination therapy are becoming increasingly necessary. We demonstrated the value of a systematic high-throughput approach, adapted from prior work testing antibiotic combinations against tuberculosis and other mycobacteria, by using this approach to test antibiotic pairs against a panel of MRSA isolates with diverse patterns of antibiotic susceptibility. We identified three antibiotic pairs-daptomycin+cefazolin, vancomycin+cefazolin, and ceftaroline+rifampicin-where the addition of the second antibiotic improved the potency of the first antibiotic across all or most isolates tested. Our results indicate that these pairs warrant further evaluation in the clinical setting.

Paradoxes of the antibiotic pipeline

Paradoxes of the antibiotic pipeline

Restoring colistin sensitivity in colistin-resistant Salmonella and Escherichia coli: combinatorial use of berberine and EDTA with colistin.

Colistin is last-resort antibiotic used to treat serious clinical infections caused by MDR bacterial pathogens. The recent emergence of transferable plasmid-mediated COL resistance gene mcr-1 has raised the specter of a rapid worldwide spread of COL resistance. Coupled with the fact of barren antibiotic development pipeline nowadays, a critical approach is to revitalize existing antibiotics using antibiotic adjuvants. Our research showed that berberine combined with EDTA effectively reversed COL resistance both in vivo and in vitro through multiple modes of action. The discovery of berberine in combination with EDTA as a new and safe COL adjuvant provides a therapeutic regimen for combating Gram-negative bacteria infections. Our findings provide a potential therapeutic option using existing antibiotics in combination with antibiotic adjuvants and address the prevalent infections caused by MDR Gram-negative pathogens worldwide.

In Silico Analysis of the Ga3+/Fe3+ Competition for Binding the Iron-Scavenging Siderophores of P. aeruginosa-Implementation of Three Gallium-Based Complexes in the "Trojan Horse" Antibacterial Strategy.

The emergence of multidrug-resistant (MDR) microorganisms combined with the ever-draining antibiotic pipeline poses a disturbing and immensely growing public health challenge that requires a multidisciplinary approach and the application of novel therapies aimed at unconventional targets and/or applying innovative drug formulations. Hence, bacterial iron acquisition systems and bacterial Fe2+/3+-containing enzymes have been identified as a plausible target of great potential. The intriguing "Trojan horse" approach deprives microorganisms from the essential iron. Recently, gallium's potential in medicine as an iron mimicry species has attracted vast attention. Different Ga3+ formulations exhibit diverse effects upon entering the cell and thus supposedly have multiple targets. The aim of the current study is to specifically distinguish characteristics of great significance in regard to the initial gallium-based complex, allowing the alien cation to effectively compete with the native ferric ion for binding the siderophores pyochelin and pyoverdine secreted by the bacterium P. aeruginosa. Therefore, three gallium-based formulations were taken into consideration: the first-generation gallium nitrate, Ga(NO3)3, metabolized to Ga3+-hydrated forms, the second-generation gallium maltolate (tris(3-hydroxy-2-methyl-4-pyronato)gallium), and the experimentally proven Ga carrier in the bloodstream-the protein transferrin. We employed a reliable in silico approach based on DFT computations in order to understand the underlying biochemical processes that govern the Ga3+/Fe3+ rivalry for binding the two bacterial siderophores.

Inhibition of Clinical MRSA Isolates by Coagulase Negative Staphylococci of Human Origin.

Staphylococcus aureus is frequently highlighted as a priority for novel drug research due to its pathogenicity and ability to develop antibiotic resistance. Coagulase-negative staphylococci (CoNS) are resident flora of the skin and nares. Previous studies have confirmed their ability to kill and prevent colonization by S. aureus through the production of bioactive substances. This study screened a bank of 37 CoNS for their ability to inhibit the growth of methicillin-resistant S. aureus (MRSA). Deferred antagonism assays, growth curves, and antibiofilm testing performed with the cell-free supernatant derived from overnight CoNS cultures indicated antimicrobial and antibiofilm effects against MRSA indicators. Whole genome sequencing and BAGEL4 analysis of 11 CoNS isolates shortlisted for the inhibitory effects they displayed against MRSA led to the identification of two strains possessing complete putative bacteriocin operons. The operons were predicted to encode a nukacin variant and a novel epilancin variant. From this point, strains Staphylococcus hominis C14 and Staphylococcus epidermidis C33 became the focus of the investigation. Through HPLC, a peptide identical to previously characterized nukacin KQU-131 and a novel epilancin variant were isolated from cultures of C14 and C33, respectively. Mass spectrometry confirmed the presence of each peptide in the active fractions. Spot-on-lawn assays demonstrated both bacteriocins could inhibit the growth of an MRSA indicator. The identification of natural products with clinically relevant activity is important in today's climate of escalating antimicrobial resistance and a depleting antibiotic pipeline. These findings also highlight the prospective role CoNS may play as a source of bioactive substances with activity against critical pathogens.

Oxytetracycline hyper-production through targeted genome reduction of Streptomyces rimosus.

Most biosynthetic gene clusters (BGC) encoding the synthesis of important microbial secondary metabolites, such as antibiotics, are either silent or poorly expressed; therefore, to ensure a strong pipeline of novel antibiotics, there is a need to develop rapid and efficient strain development approaches. This study uses comparative genome analysis to instruct rational strain improvement, using Streptomyces rimosus, the producer of the important antibiotic oxytetracycline (OTC) as a model system. Sequencing of the genomes of two industrial strains M4018 and R6-500, developed independently from a common ancestor, identified large DNA rearrangements located at the chromosome end. We evaluated the effect of these genome deletions on the parental S. rimosus Type Strain (ATCC 10970) genome where introduction of a 145 kb deletion close to the OTC BGC in the Type Strain resulted in massive OTC overproduction, achieving titers that were equivalent to M4018 and R6-500. Transcriptome data supported the hypothesis that the reason for such an increase in OTC biosynthesis was due to enhanced transcription of the OTC BGC and not due to enhanced substrate supply. We also observed changes in the expression of other cryptic BGCs; some metabolites, undetectable in ATCC 10970, were now produced at high titers. This study demonstrated for the first time that the main force behind BGC overexpression is genome rearrangement. This new approach demonstrates great potential to activate cryptic gene clusters of yet unexplored natural products of medical and industrial value.IMPORTANCEThere is a critical need to develop novel antibiotics to combat antimicrobial resistance. Streptomyces species are very rich source of antibiotics, typically encoding 20-60 biosynthetic gene clusters (BGCs). However, under laboratory conditions, most are either silent or poorly expressed so that their products are only detectable at nanogram quantities, which hampers drug development efforts. To address this subject, we used comparative genome analysis of industrial Streptomyces rimosus strains producing high titers of a broad spectrum antibiotic oxytetracycline (OTC), developed during decades of industrial strain improvement. Interestingly, large-scale chromosomal deletions were observed. Based on this information, we carried out targeted genome deletions in the native strain S. rimosus ATCC 10970, and we show that a targeted deletion in the vicinity of the OTC BGC significantly induced expression of the OTC BGC, as well as some other silent BGCs, thus suggesting that this approach may be a useful way to identify new natural products.

Detection of Coliform Bacteria in Raw Milk Samples Collected from Industrial Cities of Pakistan

Antibiotics and heavy metals-resistant bacteria in livestock environments can result in economic losses and raise public health and environmental problems. There is a crisis in the world's access to and pipeline for antibiotics. Objective: To screen raw milk samples collected from three different industrial cities Gujranwala, Lahore, and Sheikhupura, situated in the province of Punjab, Pakistan. Methods: In this regard, a total of 26 samples were having 84 coliform strains. Separated coliform colonies were processed for Gram's staining, catalase, indole production, and Simmon's citrate and motility tests. Results: Metal resistance of bacterial strains was also checked and 39.5% and 45.23% of bacteria were found to be resistant to ZnCl2 1% and 0.5%. 69.045% and 77.38% bacteria were found to be resistant to CuSo4 salt solution1% and 0.5%. 17.85% and 27% bacteria were found to be resistant to Na2CrO4 salt solution1% and 0.5% respectively. 80% of bacteria were found to be resistant to Cefuroxime, 26.19% to Cephradine, 84.52% to Aztroeonam 41.67% to Erythromycin, 91.667% to Trimethoprim 89.28% to Lincomycins. Conclusions: The raw milk samples were not only contaminated with coliforms but the bacteria were also resistant to heavy metals and certain antibiotics which might be considered indicative of industrial and anthropogenic pollution. Cephradine, 84.52% to Aztroeonam 41.67% to Erythromycin, 91.667% to Trimethoprim 89.28% to Lincomycins. Conclusions: The raw milk samples were not only contaminated with coliforms but the bacteria were also resistant to heavy metals and certain antibiotics which might be considered indicative of industrial and anthropogenic pollution.

High-throughput screening of small-molecules libraries identified antibacterials against clinically relevant multidrug-resistant A. baumannii and K. pneumoniae

The current pipeline for new antibiotics fails to fully address the significant threat posed by drug-resistant Gram-negative bacteria that have been identified by the World Health Organization (WHO) as a global health priority. New antibacterials acting through novel mechanisms of action are urgently needed. We aimed to identify new chemical entities (NCEs) with activity against Klebsiella pneumoniae and Acinetobacter baumannii that could be developed into a new treatment for drug-resistant infections. We developed a high-throughput phenotypic screen and selection cascade for generation of hit compounds active against multidrug-resistant (MDR) strains of K.pneumoniae and A.baumannii. We screened compound libraries selected from the proprietary collections of three pharmaceutical companies that had exited antibacterial drug discovery but continued to accumulate new compounds to their collection. Compounds from two out of three libraries were selected using "eNTRy rules" criteria associated with increased likelihood of intracellular accumulation in Escherichia coli. We identified 72 compounds with confirmed activity against K.pneumoniae and/or drug-resistant A.baumannii. Two new chemical series with activity against XDR A.baumannii were identified meeting our criteria of potency (EC50≤50μM) and absence of cytotoxicity (HepG2 CC50≥100μM and red blood cell lysis HC50≥100μM). The activity of close analogues of the two chemical series was also determined against A.baumannii clinical isolates. This work provides proof of principle for the screening strategy developed to identify NCEs with antibacterial activity against multidrug-resistant critical priority pathogens such as K.pneumoniae and A.baumannii. The screening and hit selection cascade established here provide an excellent foundation for further screening of new compound libraries to identify high quality starting points for new antibacterial lead generation projects. BMBF and GARDP.

Vaccine value profile for Klebsiella pneumoniae

Klebsiella pneumoniae causes community- and healthcare-associated infections in children and adults. Globally in 2019, an estimated 1.27 million (95% Uncertainty Interval [UI]: 0.91–1.71) and 4.95 million (95% UI: 3.62–6.57) deaths were attributed to and associated with bacterial antimicrobial resistance (AMR), respectively. K. pneumoniae was the second leading pathogen in deaths attributed to AMR resistant bacteria. Furthermore, the rise of antimicrobial resistance in both community- and hospital-acquired infections is a concern for neonates and infants who are at high risk for invasive bacterial disease. There is a limited antibiotic pipeline for new antibiotics to treat multidrug resistant infections, and vaccines targeted against K. pneumoniae are considered to be of priority by the World Health Organization. Vaccination of pregnant women against K. pneumoniae could reduce the risk of invasive K.pneumoniae disease in their young offspring. In addition, vulnerable children, adolescents and adult populations at risk of K. pneumoniae disease with underlying diseases such as immunosuppression from underlying hematologic malignancy, chemotherapy, patients undergoing abdominal and/or urinary surgical procedures, or prolonged intensive care management are also potential target groups for a K. pneumoniae vaccine.A ‘Vaccine Value Profile’ (VVP) for K.pneumoniae, which contemplates vaccination of pregnant women to protect their babies from birth through to at least three months of age and other high-risk populations, provides a high-level, holistic assessment of the available information to inform the potential public health, economic and societal value of a pipeline of K. pneumoniae vaccines and other preventatives and therapeutics. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public–private partnerships, and multi-lateral organizations, and in collaboration with stakeholders from the WHO. All contributors have extensive expertise on various elements of the K.pneumoniae VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

Combating antimicrobial resistance: the silent war.

Once hailed as miraculous solutions, antibiotics no longer hold that status. The excessive use of antibiotics across human healthcare, agriculture, and animal husbandry has given rise to a broad array of multidrug-resistant (MDR) pathogens, posing formidable treatment challenges. Antimicrobial resistance (AMR) has evolved into a pressing global health crisis, linked to elevated mortality rates in the modern medical era. Additionally, the absence of effective antibiotics introduces substantial risks to medical and surgical procedures. The dwindling interest of pharmaceutical industries in developing new antibiotics against MDR pathogens has aggravated the scarcity issue, resulting in an exceedingly limited pipeline of new antibiotics. Given these circumstances, the imperative to devise novel strategies to combat perilous MDR pathogens has become paramount. Contemporary research has unveiled several promising avenues for addressing this challenge. The article provides a comprehensive overview of these innovative therapeutic approaches, highlighting their mechanisms of action, benefits, and drawbacks.

Using Machine Learning to Predict the Antibacterial Activity of Ruthenium Complexes.

Rising antimicrobial resistance (AMR) and lack of innovation in the antibiotic pipeline necessitate novel approaches to discovering new drugs. Metal complexes have proven to be promising antimicrobial compounds, but the number of studied compounds is still low compared to the millions of organic molecules investigated so far. Lately, machine learning (ML) has emerged as a valuable tool for guiding the design of small organic molecules, potentially even in low-data scenarios. For the first time, we extend the application of ML to the discovery of metal-based medicines. Utilising 288 modularly synthesized ruthenium arene Schiff-base complexes and their antibacterial properties, a series of ML models were trained. The models perform well and are used to predict the activity of 54 new compounds. These displayed a 5.7x higher hit-rate (53.7 %) against methicillin-resistant Staphylococcus aureus (MRSA) compared to the original library (9.4 %), demonstrating that ML can be applied to improve the success-rates in the search of new metalloantibiotics. This work paves the way for more ambitious applications of ML in the field of metal-based drug discovery.

Maschinelles Lernen zur Vorhersage antibakterieller Aktivität von Ruthenium‐Komplexen**

AbstractDie steigende antimikrobielle Resistenz (AMR) und der Mangel an Innovation in der Antibiotikaforschung erfordern neue Ansätze zur Entwicklung von Medikamenten. Metallkomplexe haben sich als vielversprechende antimikrobielle Verbindungen erwiesen. Allerdings ist die Anzahl der untersuchten Verbindungen noch klein, besonders im Vergleich zu den Millionen organischer Moleküle die bereits getestet wurden. In den letzten Jahren hat sich maschinelles Lernen (ML) als wertvolle Ressource für die Entwicklung organischer Moleküle herauskristallisiert, selbst wenn nur wenige Daten vorliegen. Erstmals erweitern wir die Anwendung von ML auf die Entdeckung von metallbasierten antimikrobiellen Verbindungen. Mithilfe von 288 modular synthetisierten Ruthenium‐Aren‐Schiff‐Basen‐Komplexen und deren antibakteriellen Eigenschaften haben wir eine Reihe von ML–Modellen trainiert. Die Modelle zeigen gute Leistungen und werden verwendet, um die Aktivität von 54 neuen Verbindungen vorherzusagen. Diese Verbindungen weisen eine 5.7‐fach höhere Trefferquote (53.7 %) gegen Methicillin‐resistente Staphylococcus aureus (MRSA) im Vergleich zur ursprünglichen Bibliothek (9.4 %) auf. Dadurch zeigen wir, dass ML zu höheren Erfolgsraten bei der Suche nach neuen Metalloantibiotika führen kann. Folglich ebnet diese Arbeit den Weg für fortschrittlichere Anwendungen von ML im Bereich der metallbasierten Wirkstoffentwicklung.

P19 The role of policy and key stakeholder decision-making in the propagation, and deceleration, of resistance evolution

Abstract Background Antimicrobials have an intangible value on reducing global health burden of infection, yet current valuation methods do not holistically capture the enablement of healthcare as a result of antimicrobials. A lack of incentive and subsequent investment into the novel antimicrobial pipeline demonstrates the urgent need for collaboration amongst those influencing the decision-making process, namely key stakeholders such as governmental bodies, industry and academia. Studies into resistance evolution focus almost entirely on proximate causes, such as the number of antibiotics used in clinical settings, or the understanding of evolutionary pathways to resistance under controlled laboratory conditions. Comparatively, the association between resistance evolution and policy decisions from governments, industry and regulatory bodies is poorly understood. Objectives The primary aim was to evaluate the multifactorial associations between β-lactam development and evolution of β-lactam resistance to inform the current and future antibiotic development pipeline. Methods To undertake this narrative report, we focussed on β-lactam antibiotics, given their clear development timeline and continuous molecular refinement to meet arising clinical and microbiological needs. As such, the evolution of resistance to β-lactams poses a significant threat to mortality, quality of life, and societal function. This report consists of six historical case studies, all of which have significantly influenced the antimicrobial resistance landscape since Fleming’s discovery of penicillin in 1928. We include lesser-known events in our narrative, such as the establishment of the National Research and Development Corporation (NRDC), which propelled the mass commercialization of penicillin, and the subsequent emergence of penicillinases. Pivotal events such as the emergence of ESBL and MBLs into clinical settings also provide insight into the historical decision-making process by key stakeholders such as governmental bodies, industry and academia. Literature reviews were conducted with a focus on the initial introduction of a particular β-lactam into the clinic and when resistance arose. Key stakeholder activities and policy decisions made during these time periods influenced the formation of case studies. Results The case studies are as follows: (i) the influence of the NRDC in accelerated antimicrobial development; (ii) the introduction of the β-lactamase inhibitor—the influence of short-term clinical and financial benefit on prescribing behaviour; (iii) the ‘golden era’ of antibiotics—cephalosporin development and the consequences of short-term market forces; (iv) knowledge of MBL resistance prior to introduction of carbapenems in clinical settings; (v) consequences of controlled manufacturing for the global supply of piperacillin/tazobactam; and (vi) early surveillance studies and the beginning of the antimicrobial stewardship agenda. Conclusions In each case study we provide insight into how key stakeholders can improve practices by learning from past experiences, to inform the future stewardship agenda. We built a case for the need to incorporate evolutionary microbiology into policy and industrial decision-making in order to improve the mitigation of antimicrobial resistance.

Medium-sized peptides from microbial sources with potential for antibacterial drug development.

Covering: 1993 to the end of 2022As the rapid development of antibiotic resistance shrinks the number of clinically available antibiotics, there is an urgent need for novel options to fill the existing antibiotic pipeline. In recent years, antimicrobial peptides have attracted increased interest due to their impressive broad-spectrum antimicrobial activity and low probability of antibiotic resistance. However, macromolecular antimicrobial peptides of plant and animal origin face obstacles in antibiotic development because of their extremely short elimination half-life and poor chemical stability. Herein, we focus on medium-sized antibacterial peptides (MAPs) of microbial origin with molecular weights below 2000 Da. The low molecular weight is not sufficient to form complex protein conformations and is also associated to a better chemical stability and easier modifications. Microbially-produced peptides are often composed of a variety of non-protein amino acids and terminal modifications, which contribute to improving the elimination half-life of compounds. Therefore, MAPs have great potential for drug discovery and are likely to become key players in the development of next-generation antibiotics. In this review, we provide a detailed exploration of the modes of action demonstrated by 45 MAPs and offer a concise summary of the structure-activity relationships observed in these MAPs.