The fallacies of hope: will we discover new antibiotics to combat pathogenic bacteria in time?

While newly developed technologies have revolutionized the classical approaches to combating infectious diseases, the difficulties associated with developing novel antimicrobials mean that these technologies have not yet been used to introduce new compounds into the market. The new technologies, including genomics and structural biology, open up exciting possibilities for the discovery of antibiotics. However, a substantial effort to pursue research, and moreover to incorporate the results into the production chain, is required in order to bring new antimicrobials to the final user. In the current scenario of emerging diseases and the rapid spread of antibiotic resistance, an active policy to support these requirements is vital. Otherwise, many valuable programmes may never be fully developed for lack of "interest" and funds (private and public). Will we react in time to avoid potential disaster?     

细菌耐药性应对策略研究进展

细菌耐药性(Antimicrobial resistance,AMR)持续增长,但新上市抗生素数量却持续下降。抗生素耐药基因(Antimicrobial resistance gene,ARG)和抗生素耐药菌感染已严重威胁人类健康。因此,需要多方面联合采取措施来应对AMR所带来的各种挑战,包括创新生物医药、改善抗生素使用和抗生素耐药监测系统、减少抗生素耐药基因产生速度、阻止健康护理相关感染和多重抗生素耐药菌传播与扩散、开发微生物学快速诊断方法与设备、减少临床和兽医抗生素滥用等。庆幸的是,AMR已受到各国政要、科学家和企业家等的高度重视与支持,相信随着新技术、新产品的不断问世和管理新措施的不断出台,AMR问题一定会得到控制和缓解。     

New approaches to antibiotic discovery

New antibiotics are urgently required by human medicine as pathogens emerge with developed resistance to almost all antibiotic classes. Pioneering approaches, methodologies and technologies have facilitated a new era in antimicrobial discovery. Innovative culturing techniques such as iChip and co-culturing methods which use ‘helper’ strains to produce bioactive molecules have had notable success. Exploiting antibiotic resistance to identify antibacterial producers performed in tandem with diagnostic PCR based identification approaches has identified novel candidates. Employing powerful metagenomic mining and metabolomic tools has identified the antibiotic’ome, highlighting new antibiotics from underexplored environments and silent gene clusters enabling researchers to mine for scaffolds with both a novel mechanism of action and also few clinically established resistance determinants. Modern biotechnological approaches are delivering but will require support from government initiatives together with changes in regulation to pave the way for valuable, efficacious, highly targeted, pathogen specific antimicrobial therapies.     

On the possible ecological roles of antimicrobials

The Introduction of antibiotics into the clinical use in the middle of the 20th century had a profound impact on modern medicine and human wellbeing. The contribution of these wonder molecules to public health and science is hard to overestimate. Much research has informed our understanding of antibiotic mechanisms of action and resistance at inhibitory concentrations in the lab and in the clinic. Antibiotics, however, are not a human invention as most of them are either natural products produced by soil microorganisms or semisynthetic derivatives of natural products. Because we use antibiotics to inhibit the bacterial growth, it is generally assumed that growth inhibition is also their primary ecological function in the environment. Nevertheless, multiple studies point to diverse nonlethal effects that are exhibited at lower levels of antibiotics. Here we review accumulating evidence of antibiosis and of alternative functions of antibiotics exhibited at subinhibitory concentrations. We also speculate on how these effects might alter phenotypes, fitness, and community composition of microbes in the context of the environment and suggest directions for future research.     

噬菌体裂解酶的抗菌特性

摘要：噬菌体裂解酶是一类细胞壁水解酶,可水解肽聚糖,造成细菌的破裂。裂解酶一般具有两到三个结构域,参与对底物的催化和结合。作为一种新型的杀菌制剂,裂解酶已被越来越多地应用于化脓链球菌、肺炎链球菌、金黄色葡萄球菌等革兰氏阳性细菌病的治疗。与抗生素治疗相比,裂解酶不易使细菌产生抗性且作用相对专一,这可能是解决现在日趋严重的细菌耐药性的一种可行方法。另外,裂解酶还具有高效性,作用协同性,且自身抗体不削弱其作用等优势,使之成为未来预防、控制致病菌一种可能的新途径。     

Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and alternative therapeutic strategies

Pseudomonas aeruginosa is an opportunistic pathogen that is a leading cause of morbidity and mortality in cystic fibrosis patients and immunocompromised individuals. Eradication of P. aeruginosa has become increasingly difficult due to its remarkable capacity to resist antibiotics. Strains of Pseudomonas aeruginosa are known to utilize their high levels of intrinsic and acquired resistance mechanisms to counter most antibiotics. In addition, adaptive antibiotic resistance of P. aeruginosa is a recently characterized mechanism, which includes biofilm-mediated resistance and formation of multidrug-tolerant persister cells, and is responsible for recalcitrance and relapse of infections. The discovery and development of alternative therapeutic strategies that present novel avenues against P. aeruginosa infections are increasingly demanded and gaining more and more attention. Although mostly at the preclinical stages, many recent studies have reported several innovative therapeutic technologies that have demonstrated pronounced effectiveness in fighting against drug-resistant P. aeruginosa strains. This review highlights the mechanisms of antibiotic resistance in P. aeruginosa and discusses the current state of some novel therapeutic approaches for treatment of P. aeruginosa infections that can be further explored in clinical practice.     

Towards a mechanistic understanding of reciprocal drug–microbiome interactions

Broad‐spectrum antibiotics target multiple gram‐positive and gram‐negative bacteria, and can collaterally damage the gut microbiota. Yet, our knowledge of the extent of damage, the antibiotic activity spectra, and the resistance mechanisms of gut microbes is sparse. This limits our ability to mitigate microbiome‐facilitated spread of antibiotic resistance. In addition to antibiotics, non‐antibiotic drugs affect the human microbiome, as shown by metagenomics as well as in vitro studies. Microbiome–drug interactions are bidirectional, as microbes can also modulate drugs. Chemical modifications of antibiotics mostly function as antimicrobial resistance mechanisms, while metabolism of non‐antibiotics can also change the drugs’ pharmacodynamic, pharmacokinetic, and toxic properties. Recent studies have started to unravel the extensive capacity of gut microbes to metabolize drugs, the mechanisms, and the relevance of such events for drug treatment. These findings raise the question whether and to which degree these reciprocal drug–microbiome interactions will differ across individuals, and how to take them into account in drug discovery and precision medicine. This review describes recent developments in the field and discusses future study areas that will benefit from systems biology approaches to better understand the mechanistic role of the human gut microbiota in drug actions.     

Antibiotic resistance: Origins, mechanisms, approaches to counter

Microbial resistance is emerging faster than we are replacing our armamentarium of antimicrobial agents. Resistance to penicillin developed soon after it was introduced into clinical practice in 1940s. Now resistance developed to every major class of antibiotics. In healthcare facilities around the world, bacterial pathogens that express multiple resistance mechanisms are becoming common. The origins of antibiotic resistance genes can be traced to the environmental microbiota. Mechanisms of antibiotic resistance include alterations in bacterial cell wall structure, growth in biofilms, efflux pump expression, modification of an antibiotic target or acquisition of a new target and enzymatic modification of the antibiotic itself. Specific examples of each mechanism are discussed in this review. Some approaches to counter resistance include antibiotic stewardship, co-administration with resistance inhibitors, exploiting genome data in search of new targets and use of non-antibiotic antimicrobials for topical indications. A coordinated effort from government, public and industry is needed to deal with antibiotic resistance health care crisis.     

抗生素耐药防控的One Health策略

抗生素耐药作为威胁公共卫生的巨大挑战已经制约了世界经济发展。我国抗生素使用量大,是世界上抗生素滥用最严重的国家之一。文中对人群、食用动物、环境中抗生素耐药产生的原因以及抗生素耐药现状进行综述,针对我国目前抗生素使用与耐药情况,从One Health理念提出了促进抗生素的科学使用、积极探索新型抗生素研发、建立抗生素立体监测网络系统、推广抗生素耐药教育、预防感染等措施,呼吁建立跨学科、跨部门、跨地域的交流与合作,推进我国抗生素耐药防控工作进一步开展,加强环境保护,维护人类与动物的共同健康。     

Biosynthesis and combinatorial biosynthesis of pikromycin-related macrolides in Streptomyces venezuelae

Pikromycin-related macrolides have recently attracted significant research interest because they are structurally related to the semisynthetic ketolide antibiotics that have demonstrated promising potential in combating multi-drug-resistant respiratory pathogens. Cloning and in-depth studies of the pikromycin biosynthetic gene cluster from Streptomyces venezuelae have led to new avenues in modular polyketide synthases, deoxysugar biosynthesis, cytochrome P450 hydroxylase, secondary metabolite gene regulation, and antibiotic resistance. Moreover, the knowledge and tools used for these studies are proving to be valuable in the development of advanced technologies for combinatorial biosynthesis of new macrolide antibiotics. This review summarizes these new developments and introduces S. venezuelae as a powerful new system for secondary metabolite pathway engineering from bench-top genetic manipulation to product fermentation.     

Targeting virulence: a new paradigm for antimicrobial therapy

Clinically significant antibiotic resistance has evolved against virtually every antibiotic deployed. Yet the development of new classes of antibiotics has lagged far behind our growing need for such drugs. Rather than focusing on therapeutics that target in vitro viability, much like conventional antibiotics, an alternative approach is to target functions essential for infection, such as virulence factors required to cause host damage and disease. This approach has several potential advantages including expanding the repertoire of bacterial targets, preserving the host endogenous microbiome, and exerting less selective pressure, which may result in decreased resistance. We review new approaches to targeting virulence, discuss their advantages and disadvantages, and propose that in addition to targeting virulence, new antimicrobial development strategies should be expanded to include targeting bacterial gene functions that are essential for in vivo viability. We highlight both new advances in identifying these functions and prospects for antimicrobial discovery targeting this unexploited area.     

Antibiotic resistance in surface water ecosystems: Presence in the aquatic environment,prevention strategies,and risk assessment

Antibiotic-resistant bacteria (ARB) have gained increased notoriety due to their continued detection in environmental media and consequently their threat to human and animal health. The continuing spread of antibiotic resistance throughout the environment is of growing environmental and public health concern, making it difficult to treat harmful resistant diseases. This paper examines the presence of antibiotics, ARB, and antibiotic-resistant genes (ARGs) in aquatic environments; the effectiveness of current water treatment strategies to remove them; and risk assessment methods available that can be used to evaluate the risk from antibiotic resistance. Antibiotics, ARB, and ARGs have been reported at varying levels in wastewater treatment plants, hospital wastewater, irrigation water, recreational water, and drinking water. There are many different water treatments capable of reducing antibiotic resistance (including chlorination, UV, and ozone); however, no one method can fully eliminate it with much variation in the reported effects. Risk assessment models can be used for interpreting field data into the risk to human health from antibiotic resistance. Currently, there is no gold standard risk assessment method for evaluating antibiotic resistance. Methods in this area need further development to reflect evolving risk assessment methodologies and dynamic data as it emerges.     

Origins and Evolution of Antibiotic Resistance

Summary: Antibiotics have always been considered one of the wonder discoveries of the 20th century. This is true, but the real wonder is the rise of antibiotic resistance in hospitals, communities, and the environment concomitant with their use. The extraordinary genetic capacities of microbes have benefitted from man''s overuse of antibiotics to exploit every source of resistance genes and every means of horizontal gene transmission to develop multiple mechanisms of resistance for each and every antibiotic introduced into practice clinically, agriculturally, or otherwise. This review presents the salient aspects of antibiotic resistance development over the past half-century, with the oft-restated conclusion that it is time to act. To achieve complete restitution of therapeutic applications of antibiotics, there is a need for more information on the role of environmental microbiomes in the rise of antibiotic resistance. In particular, creative approaches to the discovery of novel antibiotics and their expedited and controlled introduction to therapy are obligatory.     

Resistance acquisition via the bacterial SOS response: the inducive role of antibiotics

After the euphoria of the antibiotic discovery and their tremendous action on bacterial infections outcomes, arrives a period of fear with the continuous emergence of bacteria that are resistant to almost all antibiotic treatments. It is becoming essential to better understand antibiotic resistance mechanisms to find new approaches to prevent the worldwide problem of multiresistance. The role of antibiotics on the direct induction of resistance acquisition is known. Recent studies have shown that some antibiotics, by inducing the bacterial SOS response, global repair response after DNA damages, are involved on a broader level in the induction, acquisition and dissemination of resistances in bacteria. We discuss here the role of antibiotics in resistance acquisition via the SOS response through several examples and the interest of identifying the SOS response regulators as the future targets of new families of antimicrobial molecules.     

Sweet antibiotics - the role of glycosidic residues in antibiotic and antitumor activity and their randomization

A large number of antibiotics are glycosides. In numerous cases the glycosidic residues are crucial to their activity; sometimes, glycosylation only improves their pharmacokinetic parameters. Recent developments in molecular glycobiology have improved our understanding of aglycone vs. glycoside activities and made it possible to develop new, more active or more effective glycodrugs based on these findings – a very illustrative recent example is vancomycin. The majority of attention has been devoted to glycosidic antibiotics including their past, present, and probably future position in antimicrobial therapy. The role of the glycosidic residue in the biological activity of glycosidic antibiotics, and the attendant targeting and antibiotic selectivity mediated by glycone and aglycone in antibiotics some antitumor agents is discussed here in detail. Chemical and enzymatic modifications of aglycones in antibiotics, including their synthesis, are demonstrated on various examples, with particular emphasis on the role of specific and mutant glycosyltransferases and glycorandomization in the preparation of these compounds. The last section of this review describes and explains the interactions of the glycone moiety of the antibiotics with DNA and especially the design and structure–activity relationship of glycosidic antibiotics, including their classification based on their aglycone and glycosidic moiety. The new enzymatic methodology 'glycorandomization' enabled the preparation of glycoside libraries and opened up new ways to prepare optimized or entirely novel glycoside antibiotics.     

New antibiotics from Nature’s chemical inventory

The doom and gloom of antibiotic resistance dominates public perception of this drug class. Many believe the world has entered the post-antibiotic era. Classic and modern approaches to antibacterial drug discovery have delivered a plethora of lead molecules with a great majority being natural products of ancient microbial origin. The failure of antibiotics in the resistance era comes from an inability to develop new leads into clinical candidates, which is a costly and risky endeavor for any therapeutic area, especially when resistance is at play. The world needs new antibiotic molecules to replace the exhausted pipeline and the second ‘golden era’ is certain to come from Nature’s chemical inventory once again.     

Antibiotic Resistance Determinants in a Pseudomonas putida Strain Isolated from a Hospital

Environmental microbes harbor an enormous pool of antibiotic and biocide resistance genes that can impact the resistance profiles of animal and human pathogens via horizontal gene transfer. Pseudomonas putida strains are ubiquitous in soil and water but have been seldom isolated from humans. We have established a collection of P. putida strains isolated from in-patients in different hospitals in France. One of the isolated strains (HB3267) kills insects and is resistant to the majority of the antibiotics used in laboratories and hospitals, including aminoglycosides, ß-lactams, cationic peptides, chromoprotein enediyne antibiotics, dihydrofolate reductase inhibitors, fluoroquinolones and quinolones, glycopeptide antibiotics, macrolides, polyketides and sulfonamides. Similar to other P. putida clinical isolates the strain was sensitive to amikacin. To shed light on the broad pattern of antibiotic resistance, which is rarely found in clinical isolates of this species, the genome of this strain was sequenced and analysed. The study revealed that the determinants of multiple resistance are both chromosomally-borne as well as located on the pPC9 plasmid. Further analysis indicated that pPC9 has recruited antibiotic and biocide resistance genes from environmental microorganisms as well as from opportunistic and true human pathogens. The pPC9 plasmid is not self-transmissible, but can be mobilized by other bacterial plasmids making it capable of spreading antibiotic resistant determinants to new hosts.     

Microbial environments confound antibiotic efficacy

The increasing prevalence of bacteria that are insensitive to our current antibiotics emphasizes the need for new antimicrobial therapies. Conventional approaches to antibacterial development that are based on the inhibition of essential processes seem to have reached the point of diminishing returns. The discovery that diverse antibiotics stimulate a common oxidative cell-death pathway represents a fundamental shift in our understanding of bactericidal antibiotic modes of action. A number of studies, as discussed above, also provide hints about how intra- and extracellular metabolism can enable antibiotic resistance and tolerance. We have, nonetheless, just begun to understand the repertoire of tactics that bacteria use to evade antibiotics. Biosynthetic pathways for natural antibiotics are ancient, and numerous mechanisms for antibiotic resistance and tolerance are likely to have evolved over the past few million years. Unraveling these mechanisms will require concerted efforts by chemical biologists, microbiologists and clinicians. These efforts will benefit from the use of metabolic models and other network-biology approaches to guide investigation of processes that modulate antibiotic susceptibility. Importantly, by helping to identify common points of vulnerability as well as key differences between pathogens, these models may lead to the development of effective adjuvants, novel antibiotics and new antimicrobial strategies. There is also a crucial need to better understand how bacteria within a population cooperate to overcome antibiotic treatments. Such investigations may benefit from the use of novel chemical probes and experimental techniques to interrogate the physiology and functional dynamics of natural microbial communities. Insights gained from these studies will augment metagenomic models that can be used to identify biomolecules responsible for these cooperative strategies. Leveraging chemical biology methodologies and systems-biology approaches for further studies of microbial environments may reveal a wealth of untapped targets for the development of novel compounds to counter the growing threat of resistant and tolerant bacterial infections.     

The role of antibiotics and antibiotic resistance in nature

Investigations of antibiotic resistance from an environmental prospective shed new light on a problem that was traditionally confined to a subset of clinically relevant antibiotic‐resistant bacterial pathogens. It is clear that the environmental microbiota, even in apparently antibiotic‐free environments, possess an enormous number and diversity of antibiotic resistance genes, some of which are very similar to the genes circulating in pathogenic microbiota. It is difficult to explain the role of antibiotics and antibiotic resistance in natural environments from an anthropocentric point of view, which is focused on clinical aspects such as the efficiency of antibiotics in clearing infections and pathogens that are resistant to antibiotic treatment. A broader overview of the role of antibiotics and antibiotic resistance in nature from the evolutionary and ecological prospective suggests that antibiotics have evolved as another way of intra‐ and inter‐domain communication in various ecosystems. This signalling by non‐clinical concentrations of antibiotics in the environment results in adaptive phenotypic and genotypic responses of microbiota and other members of the community. Understanding the complex picture of evolution and ecology of antibiotics and antibiotic resistance may help to understand the processes leading to the emergence and dissemination of antibiotic resistance and also help to control it, at least in relation to the newer antibiotics now entering clinical practice.