Exploring molecular mechanisms of drug resistance in bacteria and progressions in CRISPR/Cas9-based genome expurgation solutions. - Related Documents




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817001.0000Exploring molecular mechanisms of drug resistance in bacteria and progressions in CRISPR/Cas9-based genome expurgation solutions. Antibiotic resistance in bacteria is a critical global health challenge, driven by molecular mechanisms such as genetic mutations, efflux pumps, enzymatic degradation of antibiotics, target site modifications, and biofilm formation. Horizontal gene transfer (HGT) further accelerates the spread of resistance genes across bacterial populations. These mechanisms contribute to the emergence of multidrug-resistant (MDR) strains, rendering conventional antibiotics ineffective. Recent advancements in CRISPR/Cas9-based genome editing offer innovative solutions to combat drug resistance. CRISPR/Cas9 enables precise targeting of resistance genes, facilitating their deletion or inactivation, and provides a potential method to eliminate resistance-carrying plasmids. Furthermore, phage-delivered CRISPR systems show promise in selectively killing resistant bacteria while leaving susceptible strains unaffected. Despite challenges such as efficient delivery, off-target effects, and potential bacterial resistance to CRISPR itself, ongoing research and technological innovations hold promise for using CRISPR-based antimicrobials to reverse bacterial drug resistance and develop more effective therapies. These abstract highlights the molecular mechanisms underlying bacterial drug resistance and explores how CRISPR/Cas9 technology could revolutionize treatment strategies against resistant pathogens.202540051841
817210.9999From resistance to remedy: the role of clustered regularly interspaced short palindromic repeats system in combating antimicrobial resistance-a review. The growing challenge of antimicrobial resistance (AMR) poses a significant and increasing risk to public health worldwide, necessitating innovative strategies to restore the efficacy of antibiotics. The precise genome-editing abilities of the CRISPR-Cas system have made it a potent instrument for directly targeting and eliminating antibiotic resistance genes. This review explored the mechanisms and applications of CRISPR-Cas systems in combating AMR. The latest developments in CRISPR technology have broadened its potential use, encompassing programmable antibacterial agents and improved diagnostic methods for antibiotic-resistant infections. Nevertheless, several challenges must be overcome for clinical success, including the survival of resistant bacteria, generation of anti-CRISPR proteins that reduce effectiveness, and genetic modifications that change target sequences. Additionally, the efficacy of CRISPR-Cas systems differs across bacterial species, making their universal application challenging. After overcoming these challenges, CRISPR-Cas has the potential to revolutionize AMR treatment, restore antibiotic efficacy, and reshape infection control.202539404843
817120.9998Advancements in CRISPR-Cas-based strategies for combating antimicrobial resistance. Multidrug resistance (MDR) in bacteria presents a significant global health threat, driven by the widespread dissemination of antibiotic-resistant genes (ARGs). The CRISPR-Cas system, known for its precision and adaptability, holds promise as a tool to combat antimicrobial resistance (AMR). Although previous studies have explored the use of CRISPR-Cas to target bacterial genomes or plasmids harboring resistance genes, the application of CRISPR-Cas-based antimicrobial therapies is still in its early stages. Challenges such as low efficiency and difficulties in delivering CRISPR to bacterial cells remain. This review provides an overview of the CRISPR-Cas system, highlights recent advancements in CRISPR-Cas-based antimicrobials and delivery strategies for combating AMR. The review also discusses potential challenges for the future development of CRISPR-Cas-based antimicrobials. Addressing these challenges would enable CRISPR therapies to become a practical solution for treating AMR infections in the future.202540440869
918630.9998From Gene Editing to Biofilm Busting: CRISPR-CAS9 Against Antibiotic Resistance-A Review. In recent decades, the development of novel antimicrobials has significantly slowed due to the emergence of antimicrobial resistance (AMR), intensifying the global struggle against infectious diseases. Microbial populations worldwide rapidly develop resistance due to the widespread use of antibiotics, primarily targeting drug-resistant germs. A prominent manifestation of this resistance is the formation of biofilms, where bacteria create protective layers using signaling pathways such as quorum sensing. In response to this challenge, the CRISPR-Cas9 method has emerged as a ground-breaking strategy to counter biofilms. Initially identified as the "adaptive immune system" of bacteria, CRISPR-Cas9 has evolved into a state-of-the-art genetic engineering tool. Its exceptional precision in altering specific genes across diverse microorganisms positions it as a promising alternative for addressing antibiotic resistance by selectively modifying genes in diverse microorganisms. This comprehensive review concentrates on the historical background, discovery, developmental stages, and distinct components of CRISPR Cas9 technology. Emphasizing its role as a widely used genome engineering tool, the review explores how CRISPR Cas9 can significantly contribute to the targeted disruption of genes responsible for biofilm formation, highlighting its pivotal role in reshaping strategies to combat antibiotic resistance and mitigate the challenges posed by biofilm-associated infectious diseases.202438702575
921840.9998CRISPR-Cas System: A New Dawn to Combat Antibiotic Resistance. Antimicrobial resistance (AMR) can potentially harm global public health. Horizontal gene transfer (HGT), which speeds up the emergence of AMR and increases the burden of drug resistance in mobile genetic elements (MGEs), is the primary method by which AMR genes are transferred across bacterial pathogens. New approaches are urgently needed to halt the spread of bacterial diseases and antibiotic resistance. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), an RNA-guided adaptive immune system, protects prokaryotes from foreign DNA like plasmids and phages. This approach may be essential in limiting horizontal gene transfer and halting the spread of antibiotic resistance. The CRISPR-Cas system has been crucial in identifying and understanding resistance mechanisms and developing novel therapeutic approaches. This review article investigates the CRISPR-Cas system's potential as a tool to combat bacterial AMR. Antibiotic-resistant bacteria can be targeted and eliminated by the CRISPR-Cas system. It has been proven to be an efficient method for removing carbapenem-resistant plasmids and regaining antibiotic susceptibility. The CRISPR-Cas system has enormous potential as a weapon against bacterial AMR. It precisely targets and eliminates antibiotic-resistant bacteria, facilitates resistance mechanism identification, and offers new possibilities in diagnostics and therapeutics.202438605260
817450.9998Recent Advances in Understanding the Molecular Mechanisms of Multidrug Resistance and Novel Approaches of CRISPR/Cas9-Based Genome-Editing to Combat This Health Emergency. The rapid spread of multidrug resistance (MDR), due to abusive use of antibiotics has led to global health emergency, causing substantial morbidity and mortality. Bacteria attain MDR by different means such as antibiotic modification/degradation, target protection/modification/bypass, and enhanced efflux mechanisms. The classical approaches of counteracting MDR bacteria are expensive and time-consuming, thus, it is highly significant to understand the molecular mechanisms of this resistance to curb the problem from core level. The revolutionary approach of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated sequence 9 (CRISPR/Cas9), considered as a next-generation genome-editing tool presents an innovative opportunity to precisely target and edit bacterial genome to alter their MDR strategy. Different bacteria possessing antibiotic resistance genes such as mecA, ermB, ramR, tetA, mqrB and bla(KPC) that have been targeted by CRISPR/Cas9 to re-sensitize these pathogens against antibiotics, such as methicillin, erythromycin, tigecycline, colistin and carbapenem, respectively. The CRISPR/Cas9 from S. pyogenes is the most widely studied genome-editing tool, consisting of a Cas9 DNA endonuclease associated with tracrRNA and crRNA, which can be systematically coupled as sgRNA. The targeting strategies of CRISPR/Cas9 to bacterial cells is mediated through phage, plasmids, vesicles and nanoparticles. However, the targeting approaches of this genome-editing tool to specific bacteria is a challenging task and still remains at a very preliminary stage due to numerous obstacles awaiting to be solved. This review elaborates some recent updates about the molecular mechanisms of antibiotic resistance and the innovative role of CRISPR/Cas9 system in modulating these resistance mechanisms. Furthermore, the delivery approaches of this genome-editing system in bacterial cells are discussed. In addition, some challenges and future prospects are also described.202438344439
816960.9998Engineered CRISPR-Cas systems for the detection and control of antibiotic-resistant infections. Antibiotic resistance is spreading rapidly around the world and seriously impeding efforts to control microbial infections. Although nucleic acid testing is widely deployed for the detection of antibiotic resistant bacteria, the current techniques-mainly based on polymerase chain reaction (PCR)-are time-consuming and laborious. There is an urgent need to develop new strategies to control bacterial infections and the spread of antimicrobial resistance (AMR). The CRISPR-Cas system is an adaptive immune system found in many prokaryotes that presents attractive opportunities to target and edit nucleic acids with high precision and reliability. Engineered CRISPR-Cas systems are reported to effectively kill bacteria or even revert bacterial resistance to antibiotics (resensitizing bacterial cells to antibiotics). Strategies for combating antimicrobial resistance using CRISPR (i.e., Cas9, Cas12, Cas13, and Cas14) can be of great significance in detecting bacteria and their resistance to antibiotics. This review discusses the structures, mechanisms, and detection methods of CRISPR-Cas systems and how these systems can be engineered for the rapid and reliable detection of bacteria using various approaches, with a particular focus on nanoparticles. In addition, we summarize the most recent advances in applying the CRISPR-Cas system for virulence modulation of bacterial infections and combating antimicrobial resistance.202134863214
817370.9997Advancing Antibacterial Strategies: CRISPR-Phage-Mediated Gene Therapy Targeting Bacterial Resistance Genes. One of the most significant issues facing the world today is antibiotic resistance, which makes it increasingly difficult to treat bacterial infections. Regular antibiotics no longer work against many bacteria, affecting millions of people. A novel approach known as CRISPR-phage therapy may be beneficial. This technique introduces a technology called CRISPR into resistant bacteria using bacteriophages. The genes that cause bacteria to become resistant to antibiotics can be identified and cut using CRISPR. This enables antibiotics to function by inhibiting the bacteria. This approach is highly precise, unlike conventional antibiotics, so it doesn't damage our bodies' beneficial bacteria. Preliminary studies and limited clinical trials suggest that this technique can effectively target drug-resistant bacteria such as Klebsiella pneumoniae and Methicillinresistant Staphylococcus aureus (MRSA). However, challenges in phage engineering, host delivery, and the growing threat of bacterial CRISPR resistance demand urgent and strategic innovation. Our perspective underscores that without proactive resolution of these hurdles, the current hopefulness could disappear. Looking ahead, integrating next-generation Cas effectors, non-DSB editors, and resistance monitoring frameworks could transform CRISPR-phage systems from an experimental novelty into a clinical mainstay. This shift will require not only scientific ingenuity but also coordinated advances in regulatory, translational, and manufacturing efforts.202540990280
918880.9997CRISPR-Cas system, antibiotic resistance and virulence in bacteria: Through a common lens. CRISPR-Cas system, antibiotic resistance and virulence are different modes of survival for the bacteria. CRISPR-Cas is an adaptive immune system that can degrade foreign DNA, antibiotic resistance helps bacteria to evade drugs that can threaten their existence and virulence determinants are offensive tools that can facilitate the establishment of infection by pathogens. This chapter focuses on these three aspects, providing insights about the CRISPR system and resistance mechanisms in brief, followed by understanding the synergistic or antagonistic relationship of resistance and virulence determinants in connection to the CRISPR system. We have addressed the discussion of this evolving topic through specific examples and studies. Different approaches for successful detection of this unique defense system in bacteria and various applications of the CRISPR-Cas systems to show how it can be harnessed to tackle the increasing problem of antibiotic resistance have been put forth. World Health Organization has declared antibiotic resistance as a serious global problem of the 21st century. As antibiotic-resistant bacteria increase their footprint across the globe, newer tools such as the CRISPR-Cas system hold immense promise to tackle this problem.202133685595
817990.9997Nanotechnology as a Promising Approach to Combat Multidrug Resistant Bacteria: A Comprehensive Review and Future Perspectives. The wide spread of antibiotic resistance has been alarming in recent years and poses a serious global hazard to public health as it leads to millions of deaths all over the world. The wide spread of resistance and sharing resistance genes between different types of bacteria led to emergence of multidrug resistant (MDR) microorganisms. This problem is exacerbated when microorganisms create biofilms, which can boost bacterial resistance by up to 1000-fold and increase the emergence of MDR infections. The absence of novel and potent antimicrobial compounds is linked to the rise of multidrug resistance. This has sparked international efforts to develop new and improved antimicrobial agents as well as innovative and efficient techniques for antibiotic administration and targeting. There is an evolution in nanotechnology in recent years in treatment and prevention of the biofilm formation and MDR infection. The development of nanomaterial-based therapeutics, which could overcome current pathways linked to acquired drug resistance, is a hopeful strategy for treating difficult-to-treat bacterial infections. Additionally, nanoparticles' distinct size and physical characteristics enable them to target biofilms and treat resistant pathogens. This review highlights the current advances in nanotechnology to combat MDR and biofilm infection. In addition, it provides insight on development and mechanisms of antibiotic resistance, spread of MDR and XDR infection, and development of nanoparticles and mechanisms of their antibacterial activity. Moreover, this review considers the difference between free antibiotics and nanoantibiotics, and the synergistic effect of nanoantibiotics to combat planktonic bacteria, intracellular bacteria and biofilm. Finally, we will discuss the strength and limitations of the application of nanotechnology against bacterial infection and future perspectives.202336830949
9187100.9997Recent advances in gene-editing approaches for tackling antibiotic resistance threats: a review. Antibiotic resistance, a known global health challenge, involves the flow of bacteria and their genes among animals, humans, and their surrounding environment. It occurs when bacteria evolve and become less responsive to the drugs designated to kill them, making infections harder to treat. Despite several obstacles preventing the spread of genes and bacteria, pathogens regularly acquire novel resistance factors from other species, which reduces their ability to prevent and treat such bacterial infections. This issue requires coordinated efforts in healthcare, research, and public awareness to address its impact on human health worldwide. This review outlines how recent advances in gene editing technology, especially CRISPR/Cas9, unveil a breakthrough in combating antibiotic resistance. Our focus will remain on the relationship between CRISPR/cas9 and its impact on antibiotic resistance and its related infections. Moreover, the prospects of this new advanced research and the challenges of adopting these technologies against infections will be outlined by exploring its different derivatives and discussing their advantages and limitations over others, thereby providing a corresponding reference for the control and prevention of the spread of antibiotic resistance.202438994001
8168110.9997Understanding antimicrobial resistance (AMR) mechanisms and advancements in AMR diagnostics. The overuse and abuse of antibiotics, which results in the evolution of resistant microorganisms, is the primary cause of the global health catastrophe known as antimicrobial resistance (AMR). The enzymatic breakdown of antibiotics, target site modification, efflux pump overexpression, and the formation of biofilm are some of the mechanisms responsible for acquiring antimicrobial resistance (AMR). These mechanisms enable bacteria to evade or neutralize the effects of antimicrobial agents, complicating treatment options and increasing mortality rates. The rapid dissemination of resistance genes via horizontal gene transfer further exacerbates the problem, necessitating urgent intervention. Advanced AMR diagnostics are transforming the fight against antimicrobial resistance. Biosensors enable rapid, point-of-care detection; Cluster regularly interspaced short palindromic repeat (CRISPR) technologies offer precise identification of resistance genes; and mass spectrometry provides fast, accurate profiling. Automated systems streamline workflows and boost throughput, while flow cytometry delivers real-time, single-cell analysis of phenotypic resistance. Together, these innovations accelerate detection and support targeted antimicrobial stewardship, essential for combating the global AMR threat. This review covers the mechanisms underlying antimicrobial resistance (AMR) and recent advancements in AMR diagnostic technologies.202540544537
9539120.9997Materials for restoring lost Activity: Old drugs for new bugs. The escalation of bacterial resistance to conventional medical antibiotics is a serious concern worldwide. Improvements to current therapies are urgently needed to address this problem. The synergistic combination of antibiotics with other agents is a strategic solution to combat multi-drug-resistant bacteria. Although these combinations decrease the required high dosages and therefore, reduce the toxicity of both agents without compromising the bactericidal effect, they cannot stop the development of further resistance. Recent studies have shown certain elements restore the ability of antibiotics to destroy bacteria that have acquired resistance to them. Due to these synergistic activities, organic and inorganic molecules have been investigated with the goal of restoring antibiotics in new approaches that mitigate the risk of expanding resistance. Herein, we summarize recent studies that restore antibiotics once thought to be ineffective, but have returned to our armamentarium through innovative, combinatorial efforts. A special focus is placed on the mechanisms that allow the synergistic combinations to combat bacteria. The promising data that demonstrated restoration of antimicrobials, supports the notion to find more combinations that can combat antibiotic-resistant bacteria.202235461913
8178130.9997Unraveling resistance mechanisms in combination therapy: A comprehensive review of recent advances and future directions. Antimicrobial resistance is a global health threat. Misuse and overuse of antimicrobials are the main drivers in developing drug-resistant bacteria. The emergence of the rapid global spread of multi-resistant bacteria requires urgent multisectoral action to generate novel treatment alternatives. Combination therapy offers the potential to exploit synergistic effects for enhanced antibacterial efficacy of drugs. Understanding the complex dynamics and kinetics of drug interactions in combination therapy is crucial. Therefore, this review outlines the current advances in antibiotic resistance's evolutionary and genetic dynamics in combination therapies-exposed bacteria. Moreover, we also discussed four pivotal future research areas to comprehend better the development of antibiotic resistance in bacteria treated with combination strategies.202438510041
9189140.9997CRISPR-Cas9 System: A Prospective Pathway toward Combatting Antibiotic Resistance. Antibiotic resistance is rising to dangerously high levels throughout the world. To cope with this problem, scientists are working on CRISPR-based research so that antibiotic-resistant bacteria can be killed and attacked almost as quickly as antibiotic-sensitive bacteria. Nuclease activity is found in Cas9, which can be programmed with a specific target sequence. This mechanism will only attack pathogens in the microbiota while preserving commensal bacteria. This article portrays the delivery methods used in the CRISPR-Cas system, which are both viral and non-viral, along with its implications and challenges, such as microbial dysbiosis, off-target effects, and failure to counteract intracellular infections. CRISPR-based systems have a lot of applications, such as correcting mutations, developing diagnostics for infectious diseases, improving crops productions, improving breeding techniques, etc. In the future, CRISPR-based systems will revolutionize the world by curing diseases, improving agriculture, and repairing genetic disorders. Though all the drawbacks of the technology, CRISPR carries great potential; thus, the modification and consideration of some aspects could result in a mind-blowing technique to attain all the applications listed and present a game-changing potential.202337370394
9191150.9997Blunted blades: new CRISPR-derived technologies to dissect microbial multi-drug resistance and biofilm formation. The spread of multi-drug-resistant (MDR) pathogens has rapidly outpaced the development of effective treatments. Diverse resistance mechanisms further limit the effectiveness of our best treatments, including multi-drug regimens and last line-of-defense antimicrobials. Biofilm formation is a powerful component of microbial pathogenesis, providing a scaffold for efficient colonization and shielding against anti-microbials, which further complicates drug resistance studies. Early genetic knockout tools didn't allow the study of essential genes, but clustered regularly interspaced palindromic repeat inference (CRISPRi) technologies have overcome this challenge via genetic silencing. These tools rapidly evolved to meet new demands and exploit native CRISPR systems. Modern tools range from the creation of massive CRISPRi libraries to tunable modulation of gene expression with CRISPR activation (CRISPRa). This review discusses the rapid expansion of CRISPRi/a-based technologies, their use in investigating MDR and biofilm formation, and how this drives further development of a potent tool to comprehensively examine multi-drug resistance.202438511958
9217160.9997Role of CRISPR-Cas systems and anti-CRISPR proteins in bacterial antibiotic resistance. The emergence and development of antibiotic resistance in bacteria is a serious threat to global public health. Antibiotic resistance genes (ARGs) are often located on mobile genetic elements (MGEs). They can be transferred among bacteria by horizontal gene transfer (HGT), leading to the spread of drug-resistant strains and antibiotic treatment failure. CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated genes) is one of the many strategies bacteria have developed under long-term selection pressure to restrict the HGT. CRISPR-Cas systems exist in about half of bacterial genomes and play a significant role in limiting the spread of antibiotic resistance. On the other hand, bacteriophages and other MGEs encode a wide range of anti-CRISPR proteins (Acrs) to counteract the immunity of the CRISPR-Cas system. The Acrs could decrease the CRISPR-Cas system's activity against phages and facilitate the acquisition of ARGs and virulence traits for bacteria. This review aimed to assess the relationship between the CRISPR-Cas systems and Acrs with bacterial antibiotic resistance. We also highlighted the CRISPR technology and Acrs to control and prevent antibacterial resistance. The CRISPR-Cas system can target nucleic acid sequences with high accuracy and reliability; therefore, it has become a novel gene editing and gene therapy tool to prevent the spread of antibiotic resistance. CRISPR-based approaches may pave the way for developing smart antibiotics, which could eliminate multidrug-resistant (MDR) bacteria and distinguish between pathogenic and beneficial microorganisms. Additionally, the engineered anti-CRISPR gene-containing phages in combination with antibiotics could be used as a cutting-edge treatment approach to reduce antibiotic resistance.202439149034
8166170.9997A Comprehensive Review of Molecular Mechanisms Leading to the Emergence of Multidrug Resistance in Bacteria. Multidrug resistance (MDR) in bacteria poses a serious global health threat, compromising the effectiveness of antibiotics. MDR causes approximately 700,000 deaths annually, with MDR tuberculosis alone claiming 230,000 lives. While bacteria inherently possess intrinsic resistance, acquired resistance stands out as the primary culprit in MDR development. Acquired resistance mechanisms mediated by the bacterial cell wall, nucleic acids, and proteins play a pivotal role in the genesis of MDR. Bacteria can modify their cell wall structure, produce resistant enzymes, exhibit mutations in antibiotic-targeted genes, and acquire resistant genes through horizontal gene transfer. Bacteria can produce proteins that act as enzymes, chemically modifying or directly degrading the antibiotic molecules, leading to the loss of their functionality. Apart from these mechanisms, biofilms also play a pivotal role in MDR expansion. Despite the development of several antibiotics since the discovery of penicillin, continuous structural and molecular modifications in bacteria render these antibiotics ineffective against MDR. The most recent approaches such as clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (CRISPR-Cas), nanotechnology, a combination of CRISPR-Cas, and nanoparticles, show promise in treating MDR. Thus, this review delves deep into the molecular mechanisms of MDR, emphasizing the limitations of current antibiotics due to bacterial evolution and highlighting current strategies in the fight against MDR bacteria. This will drive comprehensive research to uncover additional resistance mechanisms and develop innovative strategies to combat resistant bacteria effectively. SUPPLEMENTARY INFORMATION: The online version supplementary material available at 10.1007/s12088-024-01384-6.202540655388
9216180.9997Mitigating Antibiotic Resistance: The Utilization of CRISPR Technology in Detection. Antibiotics, celebrated as some of the most significant pharmaceutical breakthroughs in medical history, are capable of eliminating or inhibiting bacterial growth, offering a primary defense against a wide array of bacterial infections. However, the rise in antimicrobial resistance (AMR), driven by the widespread use of antibiotics, has evolved into a widespread and ominous threat to global public health. Thus, the creation of efficient methods for detecting resistance genes and antibiotics is imperative for ensuring food safety and safeguarding human health. The clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas) systems, initially recognized as an adaptive immune defense mechanism in bacteria and archaea, have unveiled their profound potential in sensor detection, transcending their notable gene-editing applications. CRISPR/Cas technology employs Cas enzymes and guides RNA to selectively target and cleave specific DNA or RNA sequences. This review offers an extensive examination of CRISPR/Cas systems, highlighting their unique attributes and applications in antibiotic detection. It outlines the current utilization and progress of the CRISPR/Cas toolkit for identifying both nucleic acid (resistance genes) and non-nucleic acid (antibiotic micromolecules) targets within the field of antibiotic detection. In addition, it examines the current challenges, such as sensitivity and specificity, and future opportunities, including the development of point-of-care diagnostics, providing strategic insights to facilitate the curbing and oversight of antibiotic-resistance proliferation.202439727898
9484190.9997Phage-antibiotic combinations: a promising approach to constrain resistance evolution in bacteria. Antibiotic resistance has reached dangerously high levels throughout the world. A growing number of bacteria pose an urgent, serious, and concerning threat to public health. Few new antibiotics are available to clinicians and only few are in development, highlighting the need for new strategies to overcome the antibiotic resistance crisis. Combining existing antibiotics with phages, viruses the infect bacteria, is an attractive and promising alternative to standalone therapies. Phage-antibiotic combinations have been shown to suppress the emergence of resistance in bacteria, and sometimes even reverse it. Here, we discuss the mechanisms by which phage-antibiotic combinations reduce resistance evolution, and the potential limitations these mechanisms have in steering microbial resistance evolution in a desirable direction. We also emphasize the importance of gaining a better understanding of mechanisms behind physiological and evolutionary phage-antibiotic interactions in complex in-patient environments.202133175408