Review Alternatives to Conventional Antibiotics in the Era of Antimicrobial Resistance Chandradhish Ghosh, 1 Paramita Sarkar, 1 Rahaf Issa, 2 and Jayanta Haldar 1, * As more antibiotics are rendered ineffective by drug-resistant bacteria, focus must be shifted towards alternative therapies for treating infections. Although several alternatives already exist in nature, the challenge is to implement them in clinical use. Advancements within biotechnology, genetic engineering, and synthetic chemistry have opened up new avenues towards the search for therapies that can substitute for antibiotics. This review provides an introduc- tion to the various promising approaches that have been adopted in this regard. Whilst the use of bacteriophages and antibodies has been partly implemented, other promising strategies, such as probiotics, lysins, and antimicrobial pep- tides, are in various stages of development. Propitious concepts such as genetically modified phages, antibacterial oligonucleotides, and CRISPR- Cas9 are also discussed. The Problem of Antimicrobial Resistance and the Way Forward Currently, every year, 700 000 patients die globally due to antimicrobial resistance (AMR). It has been estimated that this death toll will increase to 10 million by 2050, which would lead to a reduction of gross domestic product (GDP) by at least 2.5% i . The fight against AMR is constant, and the discovery of new antibiotics is critical. Together, the facts and statistics raise an important question: is the time of antibiotics up? Although antibiotics have served humanity well for the last 70 years or so, the ability of bacteria to quickly evolve has made it imperative to look for other options. In this review, we provide a brief introduction into the strategies that could be therapeutic alternatives to antibiotics. We focus on therapeutic strategies, thus, vaccines which have been widely used as preventive measures against bacterial infections such as tuberculo- sis, tetanus, pertussis, diphtheria, and pneumococcal diseases, are excluded from this review. Instead of including traditional antibiotics that normally target physiological processes in bacteria (e.g., replication, transcription, translation, biosynthetic processes) we have covered synthetic compounds which work using a different mechanism. A summary of the novel approaches that hold promise is detailed in Table 1 (Key Table). For simplicity, strategies have been arranged in three nonexhaustive categories: (i) naturally occurring alternatives, (ii) synthetically designed strategies, and (iii) biotechnology-based strategies. Finally, we con- clude the review with our perspective on the status of the field and its future prospective. Naturally Occurring Alternatives Phage Therapy Bacteriophages (phages), or viruses that ‘eat’ bacteria, were used to treat infected livestock before conventional antibiotics were used for this same purpose [1]. Bacteriophages propagate at the expense of bacteria. First, they anchor onto the bacterial cell surface and then inject phage genetic material into the bacterial cytoplasm. This subsequently takes over the host cell machinery, resulting in the synthesis of phage components and assembly of new phages within Highlights As bacteria grow resistant to conven- tional antibiotics, alternatives are being investigated, including antibodies, pro- biotics, bacteriophages, and antimi- crobial peptides currently undergoing clinical trials. The specificity of antibodies, and the inability of bacteria to develop resis- tance against them, make antibodies attractive, albeit expensive, alternative therapeutic agents. Bacteriophages have been used for therapy in some parts of the world. Antimicrobial peptides have long been considered as potential replacements for antibiotics but with limited success. Synthetic peptides and synthetic membrane-active agents might herald a shift. Probiotics and fecal transplant therapy are already in practice for enhancing the human microbiota. The use of oligonucleotides for silen- cing resistance genes and resensitiz- ing resistant bacteria to antibiotics is still in the research stage. 1 Antimicrobial Research Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bengaluru 560064, India 2 Department of Infection, Immunity and Cardiovascular Diseases, The University of Sheffield, Sheffield, UK *Correspondence: jayanta@jncasr.ac.in (J. Haldar). TIMI 1655 No. of Pages 16 Trends in Microbiology, Month Year, Vol. xx, No. yy https://doi.org/10.1016/j.tim.2018.12.010 1 © 2018 Published by Elsevier Ltd.