An overview of the antimicrobial resistance mechanisms of bacteria.

Europe to boost development of new antimicrobial drugs

Chapter 5 - Progressive approach of phenolic acids toward the advancement of antimicrobial drugs

Abstract:Pathogenic microorganisms cause serious and lethal infectious diseases. Numerous antimicrobial agents have been developed during the last few decades to treat these infectious diseases, but these are still expanding worldwide. Moreover, microorganisms are developing resistance against commercially available medicines. So, antimicrobial resistance is expanding as the most serious health threat particularly in developing countries, due to the easier availability of anti-microbial drugs. Therefore, the scarcity of effective antibiotics suggests the pressing demand for new anti-microbial agents. Modern drug discovery regarded heterocyclic compounds as its core due to their striking structural characteristics. Pyrazole is considered as a significant heterocyclic nucleus in modern drug development. This review brings a considerable summary regarding derivatives of pyrazole developed over the last decade for their anti-microbial action, along with docking studies carrying an expectation that it will be beneficial for medicinal chemists working in anti-microbial drug development.

Molecular Entities of Antimicrobial Drugsand Resistance Mechanism Underlying: Bioaccessibility, Bioavailability, and Bioaccumulation

Antimicrobial resistance is a global public health issue and one of the most serious threats to the mankind today. Some bacterial strains have acquired resistance to most antimicrobial drugs and, therefore, new antibacterial agents that would overcome resistant strains are needed. In 2017, the World Health Organization published a list of priority antimicrobial-resistant pathogens. Most of these agents are gram-negative bacteria. Due to their structure, the gram-negative bacteria are more resistant to antimicrobials than gram-positive bacteria and cause significant morbidity and mortality worldwide. The main resistance mechanisms are: restricted drug absorption, modification of the target attack, inactivation of the antimicrobial drug by production of hydrolyzing enzymes and active drug efflux. These mechanisms may be innate or acquired by microorganisms, and understanding those mechanisms may create new treatment options for infectious pathology and may contribute to the development of new antimicrobial drugs that counter the microbial attempts to become resistant.

Focusing on Europe and the United States, and using policy/regulatory document analysis, qualitative interviews and quantitative cost-scenario analysis, we explore regulatory and market influences on the commercial development of novel antimicrobial drugs and diagnostics to meet the global antimicrobial resistance (AMR) crisis. We show that the regulation of clinical trials previously inhibited firms’ ability to develop commercially viable antimicrobials, but now unattractive commercial prospects are the main barrier. Our findings improve the understanding of the challenges of drug development in the context of market failure and highlight unique problems of AMR in terms of the alignment of different incentive structures and value(s), including clinical norms and practices.

“Superbugs” are the antimicrobial-resistant microorganisms. Bacteria, viruses, fungi, and parasites acquire the ability to evade the antimicrobial drug effects, not only to survive but also, in some cases, become more virulent. As such, the existing antimicrobial drugs are no longer effective and useful in treating the infections (used to be treatable). Superbug-induced infections are the major worldwide health concern with higher human mortality and an increased financial burden on society. The underlying mechanism of the evolvement of drug-sensitive to drug-resistant microorganisms is an extremely complex phenomenon. It is partly related to microorganism's unique ability to modify their genetic structures and biochemical functionality to survive and keep growing even in the presence of antimicrobial drugs. Since there are multiple factors involved in developing antimicrobial drug resistance, it cannot be reversed by adopting a single prevention strategy. Of importance, certain bacterium may not require antimicrobial drug exposure to develop resistance, as surrounding environmental exposure can facilitate the resistance. Consistent misuse and overuse of antimicrobial drugs by healthcare professionals and consumers with its extensive use in food and meat production have put human health at risk. Lack of resources for research and low interest in developing the newer generation of antimicrobial drugs are also contributing to the evolution of superbugs. Without global involvement, partnership and collaboration, superbug-induced morbidity and mortality will be unmanageable in the future. To address this impending global health crisis, in May 2015, the World Health Organization (WHO) assembly adopted a global action plan to combat the antimicrobial resistance, that include (1) to increase the awareness of antimicrobial resistance, (2) to advance research and surveillance, (3) to cut down the rate of infections through preventive measures, (4) to ensure the optimal use of antimicrobial drugs, and (5) to develop sustainable investment, taking into account the needs of the countries, to develop novel interventions. Unfortunately, implementing such WHO measures have both financial and logistic hurdles, and the rates of superbug-induced infections are alarmingly increasing. A recently published article in “Frontiers in Public Health” has highlighted the importance of microbial resistance movements to reduce the burden of superbug-induced infections (1). The authors have elaborated on the genesis of antimicrobial drugs and listed the challenges of producing the newer generation of drugs to combat existing drug-resistant pathogens (1). Although the authors briefly touched on the irrational prescription of antimicrobial drugs in the both developed and developing countries, the review article did not discuss in depth the regulatory enforcement procedures to minimize the antimicrobial resistance (1). The opportunities and challenges of global standardization of the antimicrobial prescription processes were not explained in detail in the publication (1). Another critical area that was not emphasized enough in the article was the use of the antimicrobial drugs on animals and its potential consequences in developing antimicrobial resistance. This commentary will briefly elaborate on the cross-species transmission of resistant pathogens from animal to human. Appreciating that one single review article cannot cover all the aspects of antimicrobial resistance, the authors have fittingly highlighted the scientific and economic challenges that are hindering the novel antimicrobial drug development (1). The publication has justifiably concluded that antimicrobial resistance is a multifaced issue driven by numerous interrelated factors, and therefore, the use of any single intervention would have limited success (1). Recent publications have also emphasized why implementing an antimicrobial stewardship program is necessary to prepare the future medical professionals to enhance their awareness and knowledge of antimicrobial resistance to reduce the disease burden related to superbug-mediated infections (Figure 1) (2, 3). Open in a separate window Figure 1 Schematic diagram showing the main steps needed to be implemented to minimize the antimicrobial drug resistance (2).

Antimicrobial drug development over the last two decades suggests that the choice of dose and dosing regimen can be selected at a very early stage. This is achieved by optimizing several key factors that are properties of the drug, the bug, and the host species. Drug exposure metrics, relative to the potency of the drug, are computed during the early stages of anti-infective drug development. These metrics serve as predictors of efficacy in the animal models of infection. Drug exposure relative to its potency can be expressed using a few metrics such as AUC/MIC, T>MIC, or Cmax/MIC. The class of drugs that the anti-infective belongs to often determines the optimal choice of the metric for a given anti-microbial (and is empirically chosen based on pre-clinical data). There are various anti-microbial drug classes available on the market. Despite a large number of drug classes, there is reasonable consensus that the PK/PD target, i.e. metric of relative drug exposure described above, obtained from in vitro and animal experiments can predict the efficacy of specific drugs in humans. The steps involved in the derivation of this crucial PK/PD metric and dosing regimen in humans are as follows: (a) First, the metric is chosen and then the magnitude of the metric is computed using in vitro and animal PK/PD experiments; (b) Next, drug properties such as plasma protein binding are included as correction factors for the PK/PD target; (c) Finally, the non-clinical information is combined with early clinical pharmacokinetic data to estimate which dosing regimen has the greatest probability of attaining the PK/PD metric. This methodology of computing the dosing regimen and estimating the probability of successful target attainment accounts for two key sources of variability. These are between-patient variation in clinical pharmacokinetics and the gamut of MIC values that reflect the susceptibility of pathogens to the anti-microbial drug. These sources of variability are incorporated by running Monte Carlo simulations that are populationbased in nature i.e. they account for variability in both the pathogen and the host. These sophisticated simulations answer the critical question around the rate of target attainment for dosing regimens of the new antibiotic drug. In summary, combining invitro data, animal PK/PD, early clinical pharmacokinetics, and Monte Carlo simulations expedites decision making in antimicrobial drug development. These efficiencies can lead to earlier and faster entry into full development for anti-microbials and aid optimal choice of dose regimen for phase 2/3 studies.

Introduction Antimicrobial resistance (AMR) is a major threat to global health requiring continuous development of new antimicrobial agents. Antimicrobial research and development (R&D) should be promoted in the pharmaceutical industry and academia to ensure sustainable patient access to new treatment options and reduce the global AMR burden. Areas covered This review describes the historical challenges in novel antimicrobial drug development in Japan, current national efforts to promote the development, and proposals to effectively manage future AMR pandemics. Literature searches were performed in the PubMed database (from inception to January 2022). Expert opinion R&D activities in the antimicrobial space in Japan have been insufficient due to multiple factors, including unfavorable cost-profit balance and differences in regulatory requirements between Japan and Western countries. However, the situation is improving with the implementation of the Japanese AMR action plan, drug R&D programs led by the Japan Agency for Medical Research and Development, and efforts of regulatory agencies in the United States, Europe, and Japan in aligning and expediting the clinical development process. Further actions during the interpandemic period will strengthen antimicrobial R&D, including international and interdisciplinary collaboration, continued funding and investment with the national government’s leadership, and fostering of new-generation academic research leaders. PLAINLANGUAGE SUMMARY Every year, many people suffer and die of antimicrobial-resistant infections worldwide. New treatment options are required to tackle antimicrobial-resistant infections; however, pharmaceutical companies have not been very active in developing antimicrobial agents in the last two decades. This was mainly due to the difficulty in discovering new and effective compounds and insufficient funds being spent on drug discovery. In addition, differences in drug development requirements between the United States (US), Europe, and Japan have made it difficult for Japanese pharmaceutical companies to develop antimicrobial agents that can be used in all regions in a timely manner. In the last decade, several measures have been taken to re-activate antimicrobial research and development in the pharmaceutical industry, as well as in academia, in Japan. These measures include a national action plan to combat antimicrobial-resistant infections and research support programs led by the Japan Agency for Medical Research and Development. Regulatory authorities in the US, Europe, and Japan have initiated efforts to expedite the development of drugs to treat infections. Moreover, pathways for accelerated regulatory review have been established to reduce the time taken for new drugs to be approved, and this has already been applied to several new anti-infective drugs. To combat the coronavirus disease 2019 (COVID-19) pandemic, the development of novel vaccines and antiviral drugs has been accelerated with unprecedented speed. Additional actions, such as international research collaboration programs and investment in new antimicrobial development, may help promote antimicrobial research and development activities in Japan.

Innovation in the antimicrobial sector has become challenging as the conventional incentive models, including intellectual property rights (IPR), fail to produce expected outcomes. Due to growing antimicrobial resistance, a persistent demand for new antimicrobials exists. However, relatively high risk and low return from the investment in antimicrobial drug development and the shorter period of use of antimicrobial drugs (as the drug of last resort) make the antimicrobial sector less attractive for investors. Moreover, antimicrobial resistance stewardship plans discourage the excessive use of antibiotics, impacting sales volumes. As a result, the limited-term monopoly of patents does not provide adequate protection for investors to recoup their investments. The R&D pipelines for antimicrobial drugs have dried up because of the reluctance among the investors and the absence of Big Pharma, and the new incentive models with a pull-and-push approach are gaining momentum. The policy interventions for antimicrobial drug development entrench between two continuums: innovation and access. The innovation structure demands novel approaches based on new/alternative incentive models at the pre-clinical and clinical stages. Patent licensing strategies could facilitate innovation and access to antimicrobial drugs, such as open and non-exclusive patent licensing and patent pooling. Given the disparities among the nations in their approach to antimicrobial resistance and antimicrobial drug development, a global health and innovation initiative with a cross-sectional and coordinated approach is pertinent. The policy interventions for antimicrobial innovation need a long-term crosssectionaland mission-oriented approach.

The prevalence of antimicrobial resistance reduces the effectiveness of antimicrobial drugs in the prevention and treatment of infectious diseases caused by pathogens such as bacteria, fungi, and viruses. Microbial secondary metabolites have been recognized as important sources for new drug discovery and development, yielding a wide range of structurally novel and functionally diverse antimicrobial drugs for the treatment of a variety of diseases that are considered good producers of novel antimicrobial drugs. Bacteria produce a wide variety of antimicrobial compounds, and thus, antibiotics derived from natural products still dominate over purely synthetic antibiotics among the antimicrobial drugs developed and introduced over the last four decades. Among them, Pseudomonas aeruginosa secondary metabolites constitute a richly diverse source of antimicrobial substances with good antimicrobial activity. Therefore, they are regarded as an outstanding resource for finding novel bioactive compounds. The exploration of antimicrobial compounds among Pseudomonas aeruginosa metabolites plays an important role in drug development and biomedical research. Reports on the secondary metabolites of Pseudomonas aeruginosa, many of which are of pharmacological importance, hold great promise for the development of effective antimicrobial drugs against microbial infections by drug-resistant pathogens. In this review, we attempt to summarize published articles from the last twenty-five years (2000-2024) on antimicrobial secondary metabolites from Pseudomonas aeruginosa.

Amphiphilic small molecule antimicrobials: From cationic antimicrobial peptides (CAMPs) to mechanism-related, structurally-diverse antimicrobials

Antimicrobial resistance patterns change over time and longitudinal surveillance studies provide insight into these trends. We sought to describe the important trends in antimicrobial resistance in key pathogens across Canada to provide useful information to clinicians, policy makers and industry, to assist in optimizing antimicrobial therapy, formulary choices and drug development. We analysed longitudinal data from the CANWARD study using a multivariate regression model to control for possible effects of patient demographics on resistance, in order to assess the impact of time on antimicrobial resistance independent of other measured variables. We identified several key trends in common pathogens. In particular, we observed a statistically significant increase in the proportion of Escherichia coli isolates that were resistant to extended-spectrum cephalosporins and fluoroquinolones, an increase in the proportion of Klebsiella pneumoniae isolates that were resistant to extended-spectrum cephalosporins, a reduction in the proportion of Staphylococcus aureus that were methicillin, clindamycin and trimethoprim/sulfamethoxazole resistant, and a reduction in the proportion of Pseudomonas aeruginosa that were fluoroquinolone and gentamicin resistant. Although some of these trends, such as the dramatic increase in fluoroquinolone and cephalosporin resistance in E. coli, can be attributed to the emergence and global spread of resistant clones (e.g. ST131 E. coli), others remain unexplained. However, recognizing these trends remains important to guide changes in empirical antimicrobial therapy and drug development.

Currently, the emergence of multidrug resistant microorganisms as Acinetobacter baumannii and Mycobacterium tuberculosis as well as new drug resistant forms of Neisseria gonorrhoeae in conjunction with the evolving of resistance genes as the KPC (class A Klebsiella pneumoniae) and NDM-1 (New Delhi metallo-β-lactamase 1) carbapenemases are a public health threat that requires great efforts in prevention, treatment and diagnosis. For that reason, the InterAcademy Panel and InterAcademy Medical Panel statement (IAP-IAMP) included in their Global recommendations call for action to tackle antimicrobial resistance under the following item “Encourage industry innovation and public–private collaborative research and development programs for therapeutics, diagnostics, and vaccines”. In this way, the development of novel antimicrobial drugs is not only necessary, is a priority the search and development of new pharmacological strategies for prevent antimicrobial resistance emergence, these strategies should have the ability of improve the current anti-infective therapy in combination, and recuperate the susceptibility of multidrug-resistant strains to the antibiotics. Thereupon, the introduction of screening platforms in a rational in vitro antimicrobial adjuvants drug discovery program is an important approach that will allow the detection of new chemical entities that can inhibit resistant mechanisms specifically and without side effects, looking for increase the microbicidal effect and prevent the development of subsequent mutations to anti-infective therapy. The aim of this review is to explore antibiotic adjuvants as therapeutic plan of action that can be developed for the discovery of new compounds that make bacteria more susceptible to anti-infectives by improving their efficacy.

The development and testing of new antimicrobial peptides (AMPs) represent an important milestone toward the development of new antimicrobial drugs that can inhibit the growth of pathogens and multidrug-resistant microorganisms such as Pseudomonas aeruginosa, Gram-negative bacteria. Most AMPs achieve these goals through mechanisms that disrupt the normal permeability of the cell membrane, which ultimately leads to the death of the pathogenic cell. Here, we developed a unique combination of a membrane penetrating peptide and peptides prone to amyloidogenesis to create hybrid peptide: “cell penetrating peptide + linker + amyloidogenic peptide”. We evaluated the antimicrobial effects of two peptides that were developed from sequences with different propensities for amyloid formation. Among the two hybrid peptides, one was found with antibacterial activity comparable to antibiotic gentamicin sulfate. Our peptides showed no toxicity to eukaryotic cells. In addition, we evaluated the effect on the antimicrobial properties of amino acid substitutions in the non-amyloidogenic region of peptides. We compared the results with data on the predicted secondary structure, hydrophobicity, and antimicrobial properties of the original and modified peptides. In conclusion, our study demonstrates the promise of hybrid peptides based on amyloidogenic regions of the ribosomal S1 protein for the development of new antimicrobial drugs against P. aeruginosa.