New Drugs Targeting Antibiotic-Resistant Bacteria: Recent Advances E-Book
Editor: Mariano Martínez-Vázquez
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- Herausgeber: Bentham Science Publishers
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
New Drugs Targeting Antibiotic-Resistant Bacteria: Recent Advances examines the molecular, pharmacological, and clinical dimensions of resistance development and highlights innovative therapeutic approaches aimed at overcoming multidrug-resistant organisms (MDROs), providing an in-depth exploration of emerging strategies to combat one of the most urgent public health challenges of our time—antimicrobial resistance (AMR). Beginning with the mechanisms underlying bacterial resistance such as β-lactamase production, efflux pump activity, and membrane protein modification, the text underscores the growing threat posed by ESKAPE pathogens and CDC-classified priority infections. Chapters also explore cutting-edge interventions including bacteriophage therapy, discovery of novel antibacterial compounds from natural sources, and the use of nanoparticles and quorum-sensing inhibitors to suppress bacterial virulence. Further sections discuss carbapenemase-mediated resistance, emphasizing enzyme classification, detection strategies, and the importance of clinical microbiology in guiding antibiotic stewardship. By integrating one-health perspectives that consider human, animal, and environmental dimensions, this book presents a holistic roadmap for addressing resistance evolution through innovation and responsible antibiotic use. Key Features Examines the molecular mechanisms driving antibiotic resistance in key bacterial species Explores bacteriophage therapy as a promising alternative to conventional antimicrobials Discovers natural-source compounds and novel drug leads for future antibiotic development Analyses carbapenemase-mediated resistance and clinical detection techniques Evaluates new therapeutic approaches including nanoparticle-based treatments and quorum-sensing inhibition Promotes the one-health approach to tackling multidrug-resistant organisms globally
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Veröffentlichungsjahr: 2025
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PREFACE
Bacterial strains' resistance to bactericides is a natural process that arises from the selection pressure of antibiotics against these pathogens. The continuous assault of drugs on bacteria prompts these organisms to develop various defense mechanisms, such as β-lactamase biosynthesis, which targets the hydrolysis of the β-lactam ring in different penicillin and carbapenems. Other resistance mechanisms exist, such as changes in cell membrane proteins or the increased activity of efflux pumps. These changes are derived from gene information from surviving bacteria to pharmacological treatments. The dissemination of this information is done very efficiently both by vertical and transverse routes. It is known that penicillin resistance emerged only a few years after the implementation of penicillin as a worldwide antibacterial drug. This was the beginning of a recurring phenomenon: a new drug was synthesized to treat a complex infection, and a time later, strains were resistant to this new medication. The misuse of antibiotics in livestock production and among humans, where antibiotic medication was unnecessary, has accelerated the emergence of Multidrug-Resistant Strains (MDR). Upon reaching concerning levels of bacterial resistance worldwide in 2017, the World Health Organization launched a list called ESKAPE, which identifies the main resistant drug bacteria that constitute a threat and require new drugs with new routes of action. Recently, the Centers for Disease Control and Prevention (CDC-USA), considering the rise of infections and deaths induced by microorganisms, classified the infections as urgent, serious, and concerning threats. It is worth noting that the CDC list differs from that proposed by the World Health Organization in 2017. As Chapter One indicates, antibiotic resistance is one of humanity's most immense health challenges. Virtually any bacterium can develop resistance, either by its evolution, by antibiotic pressure, or by genetic exchanges. Additionally, in this chapter, the author emphasizes the need for a one-health approach, addressing MDRO comprehensively in humans, animals, soil, water, and manure. The focus is on infection prevention and control, as well as optimizing antibiotic use to break the chain of resistance acquisition and transmission. In chapter two, the authors cover various aspects of phage therapy, including isolating and characterizing bacteriophages, the development of suitable formulations, and their administration for treating human infections. It also examines successful cases of phage therapy in treating life-threatening infections that cannot be cured with current antibiotics. Moreover, the chapter highlights the advantages and limitations of phage therapy compared to traditional antimicrobials. Chapter three focuses on the ongoing efforts and strategies to find new antibacterial compounds from natural sources. It discusses traditional methods and innovative techniques for dealing with non-culturable microorganisms. The positive outcomes of these approaches offer hope for a potential resurgence in discovering these valuable molecules, marking a second golden age for the field. As indicated in Chapter Four, clinicians have limited options when choosing antibiotics. The only available option for them is carbapenems. To develop new pharmacological strategies, clinicians must identify enzymes that break down these antimicrobials. Identifying these enzymes is crucial to reduce the selection pressure and ensure the correct use of antibiotics. The length of time a molecule stays active in the body is determined by its persistence. Clinical microbiology laboratories play a crucial role in guiding the administration of drugs. This chapter discusses the importance of carbapenemases-mediated resistance, its classification, impact, and detection strategies. Chapter Five identifies the most effective bactericidal-drug combinations against drug-resistant bacteria. Combining the carbapenem antibiotic and a β-lactamase inhibitor is considered one of the best combinations for clinical treatments. The chapter also discusses the use of Quorum-sensing inhibitors to inhibit virulence. Research on virulence inhibitors based on halogen furanone-type compounds has shown efficient virulence inhibition in vitro. However, there are currently no QS inhibitors in clinical evaluation.
Additionally, the synthesis of nanoparticles to counteract drug-resistant bacteria is explored. Nanoparticles synthesized with biological activity have shown significant results, especially those made from metals like silver and those synthesized using polymeric materials with biodegradable substances. Further studies are needed to determine their effectiveness and toxicity.
The editor would like to thank all the authors for their dedication and time in creating this book. He also thanks Ms. Graciela Flores-Rosete for compiling and organizing all the chapters.
List of Contributors
Multidrug Resistance, An Unmeasurable Epidemic (MDRO)
Daniela de la Rosa Zamboni1,*Abstract
Despite the undeniable benefits of antibiotics, the emergence of resistance presents a formidable challenge. This section examines the evolution of Multidrug-Resistant Organisms (MDROs), highlighting the complexities of systematic reporting and advocating for comprehensive surveillance to understand the true extent of the epidemic.
Initial successes of antibiotics, exemplified by penicillin, were short-lived as resistance swiftly emerged, marking the onset of the antibiotic resistance era. The current scenario reveals elevated resistance rates, particularly in low- and middle-income countries.
Medical concerns and reports highlight the ongoing apprehensions within the medical community regarding multidrug resistance, which dates back to the 1960s. Recent reports emphasize a global crisis of antibiotic scarcity and the rapid development of resistance. Livestock, pets, and other animals, as well as water and vegetables, are also contributing to the MDRO epidemic. The involvement of environmental animals and vegetables emphasizes the need for active epidemiological surveillance across all these sectors to prevent the transmission of MDRO, reinforcing the importance of environmental sanitation.
In conclusion, the origin and extent of the MDRO epidemic remain challenging to determine despite recent global surveillance efforts. The impact on health indicates a high association with mortality. There is a need for a One Health approach, addressing MDRO comprehensively in humans, animals, soil, water, and manure. The focus is on infection prevention and control, as well as optimizing antibiotic use to break the resistance acquisition and transmission chain.
Introduction
Diseases with high prevalence, incidence, and mortality, especially if they are contagious, typically require epidemiological surveillance. They have established and generally standardized reporting systems. However, there is an epidemic that started several decades ago. Despite its high prevalence and lethality, antibiotic resistance does not have mandatory reporting in every country, at least not in a generalized and extended manner. Antibiotic resistance has been documented for over a century, almost simultaneously with the discovery of some drugs that have prevented the most deaths, such as antibiotics.
Antibiotics have prevented millions of deaths and are regarded as one of the most significant discoveries in healthcare. Furthermore, critical medical advances, such as organ transplants, implants, cancer treatments, and complex surgeries, would not have been possible without antibiotics. The benefits and medical achievements made possible by antibiotics are undeniable. Additionally, the use of antibiotics is widespread in veterinary medicine, as well as in the cattle, poultry, and swine industries, and even agribusiness.
Antibiotic resistance is one of humanity's most significant health challenges. Virtually any bacterium can develop resistance through evolution, antibiotic pressure, or genetic exchange [1-4]. Infections caused by resistant bacteria are difficult or impossible to treat, often require complex microbiological or molecular technology for diagnosis, and are generally more lethal than their antibiotic-sensitive counterparts [5, 6]. Furthermore, antibiotic resistance affects not only humans but also animals and plants. Therefore, antibiotic resistance has been complex to study, analyze, prevent, and control.
Antibiotic resistance has gradually and continuously evolved at an alarming rate. There are multiple reports of drug resistance worldwide, and despite being local or partial reports, it is evident that the resistance epidemic has progressed to multidrug resistance, with its incidence on the rise. Unfortunately, recent systematic review studies or studies that estimate the global burden of disease due to multidrug resistance indicate that antibiotic resistance is ranked third in deaths worldwide [7].
The source of MDRO is not just the use of antibiotics in humans and poor infection control in hospitals. The use of antibiotics in chickens, cattle, and pigs, as well as the use of manure as a fertilizer for plants, plays an important role, but their reporting is poorly standardized [8].
However, with the growing epidemic, alert MDRO reporting is not yet subject to standardized epidemiological surveillance as a cause of death. Although reported by researchers with extensive international mathematical models, the reporting of data about the implications of morbidity and mortality is poorly standardized. The low perception of damage, the lack of diagnostic methods, and the little interaction between the participants in its genesis, i.e., doctors, antibiotic prescribers, veterinarians, farmers, chicken breeders, pigs, and even farmers, among other factors [8, 9], are some of the factors that could contribute to the lack of measurement of the absolute magnitude of the epidemic.
This chapter provides the reader with a general overview of the emergence and widespread evolution of MDROs, including notions about the importance and difficulty of systematic and mandatory reporting and the extension of the epidemic in humans and beyond.
The Beginning and Evolution of the Pandemic
Antibiotics have saved millions of lives since their systematic use; they are undoubtedly a remarkable achievement in the fight against bacteria [1]. However, the evolution of bacteria towards resistance has been so rapid that it has exceeded the discovery of new antibiotics. It is calculated by mathematical modeling studies that currently, deaths associated with antibiotic resistance are among the most frequent, only surpassed by stroke and ischemic heart disease [5, 6].
It is indisputable that antibiotic resistance is a natural aspect of microorganism evolution and that resistance to other organisms occurred before the widespread use of antibiotics. Some microorganisms have developed mechanisms to resist antibiotics; therefore, they produce antibiotics themselves [1, 2]. The first antibiotics used were substances produced by resistant microorganisms to kill other microorganisms [1, 2].
Since Hippocratic medicine, antibiotics have been used empirically. The empirical use of baker's yeast to treat wounds has been documented for over two thousand years in Egypt, Greece, and Serbia. About a thousand years ago, a recipe for plant-based eye drops with activity against Staphylococcus was found. This eye drop was recently recreated, and its effectiveness was demonstrated [1, 2, 11].
In 1871, Joseph Lister discovered that the fungus Penicillium brevicompactum inhibited bacterial growth. The extract was used to treat an infected wound on a nurse in 1893, hence the hypothesis that bacteria caused the infection. Bartolomeo Gosio isolated mycophenolic acid in 1893, which he used to treat Anthrax. Its use was forgotten until 1912, when it was revived by C.L. Alsberg and O.M. Black, who discovered it inhibited mitosis. Mycophenolic acid was forgotten until its immunosuppressive properties were later found [12-14]. It is currently known that there may be resistance to Mycophenolic Acid by a type of Candida, although its use to treat infections caused by it is not widespread [10, 12-14].
In 1910, Paul Ehrlich discovered the arsenic prodrug (arsphenamine), known as Salvarsan, which was used to treat syphilis. In 1913, it evolved into Neosalvarsan, which was less dangerous and more effective for treating syphilis. This marked the beginning of synthetic antibiotics [2]. Later, a broad-spectrum sulfonamide called Prontosil emerged in 1930, initially used mainly for treating soldiers during the First World War and, in 1936, for puerperal fever [3]. However, shortly after its use, mutations in the enzyme dihydropteroate synthetase—the target of the antibiotic—rendered it ineffective, leading to its replacement by penicillin, which was discovered in 1928 by Edward Fleming [2]. The structure of penicillin was elucidated in 1939 by Howard Walter Florey and Ernst Boris Chain, allowing for its purification and large-scale production. In 1945, the use of penicillin began [4]. Although penicillin was considered miraculous at the time, resistance soon emerged; in fact, penicillin resistance was identified after its discovery but before its approval for clinical use. Almost simultaneously with the advent of penicillin, the “golden age” of antibiotics commenced [5]. From the 1940s to the 1960s, several classes of antibiotics were discovered. These include antibiotics derived from actinomycetes (Aminoglycosides, Tetracyclines, Amphenicos, Macrolides, Glycopeptides, Tuveractinomycins, Ansamycins, Lincosamides, Streptogramins, Cycloserine, and Phosphonates), bacterial natural products (Polypeptides, Bacitracin, Polymyxins), natural products (Fusidic Acid, Cephalosporins, Enniatins), and synthetic antibiotics (Sulfones, Salycylates, Nitrofurans, Pyridinamides, quinolones, Azoles, Phenazines, Diaminopyrimidines, Ethambutol, and Thionamides). Unfortunately, bacterial resistance appeared shortly after the discovery of these antibiotics, in some cases even in the same year. Methicillin-resistant Staphylococcus aureus and plasmid-borne resistance to sulfonamides were detected in the early sixties [5].
After this “golden era,” the discovery of antibiotics became scarce. From the '70s to the 2000s, fewer antibiotics were discovered, including phosphonates, carbapenems, mupirocin, and monobactams in the '80s, and lipopeptides, pleuromutilin, and oxazolidinones in 2000 [5].
In the last twenty years, fewer than a dozen new antibiotics and no new types have been discovered. However, antibiotic resistance continues to advance. The World Bank estimates that 39 to 70% of E. coli are currently resistant to co-trimoxazole, and a significant percentage of MRSA are resistant to Oxacillin [5].
Medical Concerns and Reports
In the 1960s, the first reports possibly indicating concern by the medical profession about the potential consequences of multidrug resistance were documented. Gynecologists and general practitioners, among others, published papers, issued communiqués, and delivered conferences on the subject [3, 15]. In the early 21st century, with the alarming title “bad bugs, no drugs, no ESKAPE,” marking a series of reports, some international organizations, such as the Infectious Diseases Society of America and the CDC, reported the shortage of antibiotics and the rapid development of resistance. They also recognized it as a global crisis with an undefined magnitude [16, 17].
Finally, in 2015, the first global epidemiological surveillance system was initiated. This year, the WHO initiated a system for epidemiological surveillance of bacterial resistance, known as GLASS, which stands for Global Antimicrobial Resistance and Use Surveillance System. Subsequently, the consumption of antimicrobials and antifungals was monitored, and a system was implemented that considered the health of people, animals, and the environment. It currently has information from 127 countries and is in the initial implementation phase [18].
According to GLASS, over the last five years, antibiotic resistance has remained stable or increased slightly, but the resistance of a few bacteria has decreased. However, rates of antimicrobial resistance are high, particularly in low- and middle-income countries [18]. Antibiotic resistance poses alarming proportions, especially in low- and middle-income nations. The proportion of Escherichia coli infections resistant to third-generation cephalosporins has a median of 58.3% (39.8 to 70%) in low- and middle-income countries and 17.5% (11.3 to 25.21%) in high-income countries [3]. For methicillin-resistant Staphylococcus aureus, the numbers are 33.3% (19.5 to 55.6%) and 15% (6.8 to 36.4%), respectively. Both resistance profiles serve as global indicators of sustainable development linked to Sustainable Development Target 3.d (“strengthen the capacity of all countries, in particular developing countries, for early warning, risk reduction, and disaster management”) [18].
In 2022, one of the first global epidemiological approaches to analyze the impact of MDRO on mortality was conducted. The article explores all the information available so far, covering nearly every country worldwide. It shows that MDRO is associated with the third leading cause of death globally, accounting for approximately 4.5 million deaths [5]. As a direct cause of death, it ranks among the top 15 causes of death. Once again, low- and very low-income countries experience a greater impact than high-income countries [5]. The figures reported in this article may be underestimated, as independent reports were considered from countries that, in most cases, were not standardized.
Livestock, Pets, and Other Animals, and the Epidemic of MDRO
Antibiotics have been used widely in chickens and cattle for several decades. Antibiotic resistance has since been found in meat. Manure, commonly used for fertilization, also contains resistant bacteria. As a result of this resistance, 97% of the resistance to ciprofloxacin in E. coli was found in humans [5, 19].
The effects of the use of antibiotics in animals are found not only in manure but also in food-borne infections, most of which are caused by consuming contaminated meat products [5, 19].
The main bacterial agents that cause foodborne diseases—Salmonella, Listeria, Staphylococcus, E. coli, and Campylobacter—have been reported to exhibit bacterial resistance in some countries, such as Bangladesh, reaching up to 97% [8]. However, in the United Kingdom, fluoroquinolone resistance is predicted to be 75% by 2040 [20, 21].
Regarding vegetables and fruits, resistant bacteria have also been found, which genotypically coincide with the bacteria in irrigation water or manure with which they are fertilized. Outbreaks associated with the consumption of vegetables have identified irrigation water, manure, or handling during storage, packaging, transportation, or distribution as the source [8, 22].
Although not frequent, contamination has been found from the same sources as contamination by reptiles or amphibians, such as Salmonella, and outbreaks involving pets infected with Campylobacter [22, 23]. Lastly, antibiotics are widely used in aquaculture and the ornamental fish industry. However, the role of this use or the fish in transmitting MDRO is unknown [22].
“Waters.”
Drainage water may also contribute to the epidemic, particularly from hospitals or farms. Sewage from these facilities has been shown to contain a higher concentration of multidrug-resistant bacteria than water from other sources. Similarly, reports indicate MDRO disease outbreaks originating from such sites. Environmental bacteria exhibit a greater tendency for genetic transmission than their non-environmental counterparts. The role of sewage in disease transmission still necessitates further investigation. Nevertheless, active epidemiological surveillance of MDROs in wastewater could be crucial for quantifying and preventing the transmission of MDROs. It is clear that environmental sanitation, particularly water treatment and safe disposal of excreta, is vital for avoiding MDRO [22].
Wastewater can reach rivers and streams, where it may cause contamination. In Mexico, in the Lerma River, one of the country's main rivers, bacteria of the ESKAPE group were found to be resistant in up to 15% of the samples [25].
Recreational Waters
Few reports exist about the transmission of MDRO through recreational water use. However, recreational water use is linked to community outbreaks of resistant enterobacteria, with a more than doubled risk in individuals who use swimming pools. The risk appeared higher when recreational water was located near a farm [22-26]. The recreational use of seawater is also related to an increased risk of carrying resistant enterobacteria. The type of activity seems to influence this risk. For example, when comparing surfers to non-surfers, the former had a colonization percentage of 6.5% compared to 1.5% for non-surfers. Surfers ingest 150 ml or more during their activity, while non-surfers consume only around 30 ml [26].
The Need for a Systematic and Mandatory Report of MDRO and the Burden of Disease
Diseases of high epidemiological risk are those that are subject to epidemiological surveillance. In the world, they have established and generally standardized reporting systems. Although, in general, it is considered that there is an underreporting, the diseases subject to epidemiological surveillance, among which are HIV - AIDS, malaria, tetanus, and neural tube defects, have tools for diagnostic scrutiny and standardized reporting or are in the process of being standardized. Countries also have healthcare quality indicators that rarely include diseases subject to epidemiological surveillance.
However, the MDRO epidemic began less than a decade ago with global reporting, which tends to be systematized, limited to reports of bacterial resistance and the use of antibiotics in humans, primarily by hospitals.
Despite its impact, antibiotic use in the agro-industry is under little surveillance. The resistance generated by antibiotics in agribusiness is even more poorly determined [22, 23].
MDRO infections, despite their relevance and frequency, are not yet included in the ICD-10 catalog, so the actual impact on mortality, morbidity, and even costs is difficult to calculate.
Systematic mandatory reporting can lead to national or international policies for effective control measures. On the contrary, if it continues as a diagnosis that is the subject of research, it will be challenging to know and will impact the actual impact of the disease.
Hospitals, health providers, veterinarians, the poultry industry, livestock and agriculture, aquaculture, and especially the government, must establish the necessary mechanisms at the national or international level to address multidrug resistance and notify authorities of any infectious disease outbreaks.
Conclusion
The epidemiological origin and extent of the multidrug-resistant epidemic are difficult to determine. Until recently, several centuries after the first bacterial resistance was found, epidemiological surveillance has been extended worldwide with the GLASS report. The impact on health is not yet clear, although it seems to indicate that at least the third place in deaths is associated with MDRO, and MDRO as a direct cause of death occupies the first place in mortality. Unlike other notifiable diseases, MDRO still has few indicators, and its study must be extended to human beings, cattle, chickens, pets, soil, manure, and water.
To address the epidemiologic impact of MDRO, it is essential to extend efforts toward a health approach with a strong emphasis on infection prevention and control, as well as antibiotic optimization, to disrupt the chain of resistance acquisition and MDRO transmission.
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Daniel Huelgas-Méndez1,Juan Carlos García-Cruz1,José Luis Díaz-Nuñez2,Xareni Rebollar Juárez1,Daniela Luis-Yong3,Mariel Hernández-Garnica1,Jorge Santiago Jiménez-Zúñiga1,Rodolfo García-Contreras1,*Abstract
Bacteriophages are the most abundant biological entities on the planet and are specific viruses that target only bacteria. The use of these viruses to combat bacterial infections is known as phage therapy, a concept that was implemented in the early 20th century. However, its application in Western medicine was halted following the discovery and use of antibiotics. Still, due to the alarming increase in antibiotic resistance we are experiencing, phage therapy is gaining acceptance in Western countries, and several successful cases have been documented. In this chapter, we discuss various aspects of phage therapy, from bacteriophage isolation and characterization to the development of phage-suitable formulations and their administration for treating human infections. We also examine successful cases of phage therapy in treating life-threatening infections that are untreatable with current antibiotics, highlighting the advantages and limitations of phage therapy compared to traditional antimicrobials.
Introduction
Bacteriophages are viruses that infect bacteria and were discovered independently by Frederick Twort and Felix d’Herelle. In 1915, Frederick Twort reported the appearance of lytic plaques at the edge of some Staphylococcus colonies and obtained the same pattern when he spotted the filtrate supernatant of the cultures of that bacterium on the lawn of different Staphylococcus strains; unfortunately,
