RSC Advances View Article Online REVIEW View Journal | View Issue Antibiotic resistance: bioinformatics-based understanding as a functional strategy for drug Cite this: RSC Adv., 2020, 10, 18451 design Umar Ndagi, *a Abubakar A. Falaki,b Maryam Abdullahi,c Monsurat M. Lawald and Mahmoud E. Soliman e The use of antibiotics to manage infectious diseases dates back to ancient civilization, but the lack of a clear distinction between the therapeutic and toxic dose has been a major challenge. This precipitates the notion that antibiotic resistance was from time immemorial, principally because of a lack of adequate knowledge of therapeutic doses and continuous exposure of these bacteria to suboptimal plasma concentration of antibiotics. With the discovery of penicillin by Alexander Fleming in 1924, a milestone in bacterial infections' treatment was achieved. This forms the foundation for the modern era of antibiotic drugs. Antibiotics such as penicillins, cephalosporins, quinolones, tetracycline, macrolides, sulphonamides, Creative Commons Attribution-NonCommercial 3.0 Unported Licence. aminoglycosides and glycopeptides are the mainstay in managing severe bacterial infections, but resistant strains of bacteria have emerged and hampered the progress of research in this field. Recently, new approaches to research involving bacteria resistance to antibiotics have appeared; these involve combining the molecular understanding of bacteria systems with the knowledge of bioinformatics. Consequently, many molecules have been developed to curb resistance associated with different bacterial infections. However, because of increased emphasis on the clinical relevance of antibiotics, the Received 15th February 2020 synergy between in silico study and in vivo study is well cemented and this facilitates the discovery of Accepted 1st May 2020 potent antibiotics. In this review, we seek to give an overview of earlier reviews and molecular and DOI: 10.1039/d0ra01484b structural understanding of bacteria resistance to antibiotics, while focusing on the recent bioinformatics This article is licensed under a rsc.li/rsc-advances approach to antibacterial drug discovery. Open Access Article. Published on 14 May 2020. Downloaded 9/27/2021 4:40:57 AM. 1. Introduction This is as a result of dose-related issues, the knowledge of the amount required to clear the organism from the system being The use of antimicrobial entities dates back to ancient civili- inadequate. Therefore, marked symptoms of bacterial infection zation1 during which a variety of naturally available healing persist until such time that a signicant amount is reached, and methods were used in curbing infections.1 Some of these symptoms begin to disappear. Exposure of bacteria to the methods require the use of moulds and plant extracts with inadequate dose of these agents is presumed as the number one characteristics antibiotic properties. This is true for compounds cause of bacterial resistance, which could be a contributing that were accidentally discovered (such as penicillin by Alex- factor to bacterial evolution and perhaps the origin of bacteria ander Fleming in 1924) and even for those that are linked to the evolution.3 knowledge handed down by successive generations; Egyptians In the 1940s, antibiotics were major lifelines for treating applied mouldy bread to infected wounds.2 serious infections,4 this was re-established by the successful use However, until the 20th century, bacterial infections were the of penicillin in controlling bacterial infections among military number one cause of human death in the developed world.2 personnel during the Second World War.5 Luria and Delbruck¨ in the year 1943, conducted a uctuation test6 and acknowl- aCentre for Trans-Sahara Disease, Vaccine and Drug Research, Ibrahim Badamasi edged that bacterial resistance arises from heritable changes in 6 Babangida University, Lapai, Niger State, Nigeria. E-mail: [email protected] the bacterial cell (mutation), which is independent of factors bDepartment of Microbiology, School of Agriculture and Applied Sciences, University of such as co-habitation of the bacterial colony with the virus. KwaZulu-Natal, Durban 4001, South Africa Despite the advantages derived from the use of penicillin, cFaculty of Pharmaceutical Sciences, Ahmadu Bello University Zaria, Kaduna State, resistance to these drugs emerged,7 such that in the 1950s, the Nigeria giant strides made in antibiotics development in the prior dSchool of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, decade were threatened.8 In response to this, new beta (b)-lac- Durban 4001, South Africa eMolecular Modeling and Drug Design Research Group, School of Health Sciences, tam antibiotics were discovered and eventually upheld, thereby “ University of KwaZulu Natal, Westville Campus, Durban 4001, South Africa re-establishing the initial con dence of magic-use and magic This journal is © The Royal Society of Chemistry 2020 RSC Adv.,2020,10,18451–18468 | 18451 View Article Online RSC Advances Review result” antibiotics are being portrayed.5,8 Within the same Nevertheless, bacteria resistant to antibiotics might be decade, methicillin-resistant Staphylococcus aureus (MRSA) was acquired through gene mutation and by horizontal gene transfer; rst identied in the United Kingdom in 1962 and the United it can also be due to intrinsic activities resulting from inherent States in 1968.4,5 Unfortunately, resistance to most antibiotics structural or functional characteristics (Fig. 1). Unavailability of emerged in time-course4 to the extent that even the most powerful the susceptible target of a specic antibiotic is a typical example of antibiotics developed in the early 1970s like vancomycin used in intrinsic resistance, this is well represented in gram stain managing methicillin resistance in both Staphylococcus aureus (S. organism, with Gram-negative bacteria having a lower proportion aureus) and coagulase-negative staphylococci had its share of of anionic phospholipids in the cytoplasmic membrane than do resistance4,5 in the late 1970s. Gram-positive bacteria.16 This reduces the efficiency of the Ca2+ – To understand the key aspect of bacterial survival, Baym mediated insertion of daptomycin into the cytoplasmic et al. (2016) introduced microbial evolution and growth arena membrane that is required for its antibacterial activity.17 The (MEGA) – plate,9 typically used to study microbial evolution. intrinsic properties of some Gram-negative bacteria give them Their work suggests that evolution is not always led by the most protective measures that allow them to resist antibiotic effects resistant mutants; highly resistant mutant can be trapped such as antibiotic transport across the outer membrane. For behind more sensitive lineages.9 Baym concept of Petri dish example, the glycopeptide antibiotic vancomycin inhibits pepti- offers an unprecedented insight into the phenomenon of anti- doglycan cross-linking by binding to target D-Ala-D-Ala peptides, biotic resistance.10 this effect is more pronounced in Gram-positive bacteria, whereas Resistance to antibiotics is eroding the scienticeffort in in Gram-negative organisms, the drug transport across the outer keeping up the pace of antibiotics' discovery in the 21st membrane is hindered and access to the peptides in the peri- century.11 In the past (the golden era of antibiotics drug plasm is shutdown.18 The word antibiotic has become synony- discovery), resistance to antibiotics' was not too challenging,11 mous with antibacterial drugs therefore, in this article; the term this was because scientic research was coping with the chal- antibacterial refers to the antibiotic. 11 Creative Commons Attribution-NonCommercial 3.0 Unported Licence. lenges of antibiotic resistance. However, recent events in the Bioinformatics is a practical discipline that employs a range of antibiotic resistance prole have pushed most pharmaceutical computation techniques including sequence and structural industries to rededicate their efforts in developing novel mole- alignment, analyses of large collections of biological data, such as cules used in managing chronic illnesses, this approach genetic sequences, cell populations or protein samples, to make provides more nancial benets that guaranty their survival in new predictions or discover new biology.19 The application of monetary times. Thus, leading to drying up in the antibiotics bioinformatics tools and techniques in analysing the increasing pipeline and leaving behind a few potent molecules that may data generated in molecular biology, genomics, transcriptomics, limit the choice of antibiotics in curing certain disease condi- and proteomics is gaining momentum.20 Furthermore, the tions. The emergence and widespread of antibiotic-resistant quantum of information aggregated in the form of databases and This article is licensed under a pathogens is an emerging challenge in the public health literature for generating molecular proles and for collecting data domain, this requires global action with a multi-dimensional related epidemiology of pathogens has signicantly increased.21 approach that would address the fundamental challenges Therefore, the use of bioinformatics tools and techniques in Open Access Article. Published on 14 May 2020. Downloaded 9/27/2021 4:40:57 AM. inherent in curbing drug-resistance and ne-tune the lead way curbing bacteria resistance, pathogen identication and typing, to minimise drug-resistance.12 identifying markers for early diagnosis and treatment,