The term “antibiotics” refers to the substances naturally produced by microorganisms such as actinomycetes, bacteria or fungi, which can inhibit the growth of other microorganisms and destroy their cells ^[1]. The introduction of antibiotics into clinical practice was the most incredible clinical breakthrough forward of the 20th century ^[2]. The introduction of the first antibiotics hugely impacted the treatment of various life-threatening bacterial infections and society by reducing morbidity and mortality ^[3]. Nonetheless, the most recent decade of the 20th century and the beginning of the 21st century have witnessed the emergence and spread of antibiotic resistance (ABR) in different pathogenic bacteria worldwide ^[4]. Continuous misuse of these valuable compounds has rapidly increased antimicrobial resistance in various pathogens that are effectively untreatable ^[2]. Thus, some organisms have become resistant to more than one antibiotic simultaneously and have been referred to as multidrug-resistant (MDR); some organisms are even resistant to all known antibiotics and are termed pan-drug resistant ^[5]. Furthermore, although initially developed to describe Mycobacterium tuberculosis strains resistant to first-line of treatment—“resistance to the first-line agents, isoniazid and rifampicin, to a fluoroquinolone and to at least one of the three-second-line parenteral drugs”, the term extremely drug resistance evolved to define any organism resistant to any standard antimicrobial treatment regimen ^[5]. Although modern scientific technologies have boosted humanity’s hope regarding developing new antibiotics, the current scenario shows few novel antibiotics under development. Simultaneously, antibiotic-resistant bacteria that endure antibiotic treatment are getting increasingly regular, making accessible antibiotics ineffectual. Hence, humanity is confronted by significant adverse public and environmental health impacts.

2. History of Antibiotics

Since the dawn of time, bacterial infections have had a predominant spot in human diseases ^[3] and caused death in humans. During ancient times (earlier 1640), Greeks and Indians used molds and other plants to treat wounds and infections, while farmers in Russia used warm soils to cure infected wounds. Sumerian and Babylonian doctors used beer soup mixed with turtle shells and snakeskins and a mixture of frog bile and sour milk to treat diseases. Likewise, the Sri Lankan army used oil cake (sweetmeat) as a desiccant and antibacterial agent. Despite the lack of a clear idea about the reason for these illnesses, there were consistent attempts to battle them. Microorganisms exist in an unfathomably wide variety. The most prominent microbiologists, including Louis Pasteur (1822–1895) and Robert Koch (1843–1910), strongly believed that microbes must develop lethal weapons (“antibiosis”) to combat their rivals to thrive in a competitive environment, and that those that go through the competition have developed resistance to their opponents’ weapons. They reasoned that because the soil contains the greatest variety of microorganisms, this is where these mechanisms would be most effective. A scientist named Selman Waksman (1888–1973) coined the term “antibiotic” (meaning “against life”) in 1942. He explained that it is something microorganisms make at low concentrations to kill or inhibit the growth of other organisms. The term was used throughout the subsequent 20 years per the abovementioned specification. Although the term is still in use, it has expanded to include the many semi- and fully-synthetic “antibiotics” developed by the pharmaceutical industry. Rudolph Emmerich and Oscar Löw, two German researchers, created the first antibiotic, pyocyanase, in the late 1890s. It was produced by growing the bacterium Pseudomonas aeruginosa in a lab and had questionable efficacy and safety when used to treat cholera and typhus. Later, Salvarsan, an arsenic-based medication discovered by Paul Ehrlich in 1909, was effective against the syphilis-causing bacterium Treponema pallidum. In other words, this finding paved the way for future research and development of antimicrobial drugs ^[6]. Penicillin, derived from the fungus Penicillium, was the first antibiotic supplied to doctors in the 1940s. As its development was preceded by years of study and observation during World War II, it is commonly referred to as “a child of the war” ^[1]. By the late 1940s and early 1950s, antibiotic chemotherapy was well tolerated in clinical medicine after the discovery of streptomycin and tetracycline from Actinomycetes. In addition to being efficient against the bacillus causing tuberculosis, these medicines were also effective against other pathogenic bacteria ^[3]. In this context, the filamentous actinomycetes (64%) were the primary source of most naturally occurring antibiotics, followed by the bacterial and fungal species (Table 1). On the other hand, synthetic derivatives are believed to be efficient against pathogenic microbes. First-generation cephalosporins, including parenteral medications like cephalothin (1964) and cefazolin (1970) and oral medications like cephalexin (1967), are the most effective against Gram-positive bacteria, methicillin-susceptible staphylococci, and non-enterococcus streptococci ^[3]. Unlike first-generation cephalosporins, which are effective against Gram-positive and Gram-negative bacteria, second-generation cephalosporins are more successful in the clinic against Gram-negative bacteria such as Hemophilus influenzae, Enterobacter aerogenes, and some Neisseria spp. ^[8][9][10]. Further, extended-spectrum cephalosporins such as cefpirome (1983), cefepime (1987), and cefaclidine (1989) have enhanced action against Enterobacter spp., Citrobacter freundii, Serratia marcescens, and severe P. aeruginosa infections ^[11][12][13]. Antibiotics gradually established themselves as life-saving medications. In the middle of the 20th century, a large increase in the number of novel antibiotic compounds developed for medical use was observed. Between the years 1935 and 1968, a total of 12 new classes were introduced. However, there was a significant decline in the number of new classes after this; between 1969 and 2003, merely two new classes were developed ^[14].

3. Rise of Antimicrobial Resistance

The term “antimicrobial resistance” (AMR) is used to describe the ability of bacteria and other microorganisms to resist the adverse effects of an antimicrobial to which they were formerly susceptible ^[15]. Antimicrobial resistance (AMR) was first noted in staphylococci, streptococci, and gonococci; penicillin-resistant S. aureus emerged in 1942 following the introduction of penicillin as a commercial antibiotic in 1941 ^[16]. However, in the early 1930s, sulphonamide-resistant Streptococcus pyogenes appeared in human clinical settings. Later in the 1950s, the problem of multidrug-resistant enteric bacteria became evident ^[17]. Furthermore, methicillin, which is linked to penicillin and is a semi-synthetic antibiotic, was marketed in 1960 to treat S. aureus infections resistant to penicillin. Conversely, in the very same year, methicillin resistance emerged in S. aureus ^[18]. Since their introduction in the 1980s, fluoroquinolones have revolutionized the treatment of bacterial infections. Initially intended for use against Gram-negative bacteria, the emergence of fluoroquinolone resistance has shown that these medications have also been applied to combat Gram-positive infections, most notably among methicillin-resistant strains ^[19]. Furthermore, although vancomycin has been on the market for 44 years, in 2002, clinical isolates of Vancomycin-resistant S. aureus (VRSA) emerged ^[20]. A rise in deaths worldwide is attributed to bacteria resistant to multiple antibiotics. For example, there are over 63,000 annual deaths in the United States of America (USA) due to hospital-acquired bacterial infections ^[21]. Further, in 2019, the Centre for Disease Control (CDC) reported that over 2.8 million antibiotic-resistant infections occurred annually in the United States, leading to over 35,000 deaths ^[22]. The Indian Council of Medical Research (ICMR) released its annual report on antimicrobial resistance in 2020, which stated that the overall proportion of MRSA throughout the country had reached 42.1% in 2019, representing an increase of nearly 10% compared to the previous year ^[23]. According to the latest Global Antimicrobial Resistance and Use Surveillance System (GLASS) project report, data from South and Southeast Asian countries (such as India, Bangladesh, and Pakistan) reflect a considerable rise in antibiotic resistance levels. For instance, carbapenem-resistant Acinetobacter was found to be exceptionally high in Pakistan (66.9%), followed by India (59.4%). Similarly, the highest prevalence of carbapenem-resistant E. coli and carbapenem-resistant K. pneumonia was recorded in India (16.4% and 34.2%, respectively), followed by Bangladesh (9.2% and 11.2%) and Pakistan (6.2% and 11.3%) respectively. The other MDR pathogens, such as fluoroquinolone-resistant Salmonella sp. (80.3%) and MRSA (65%), were recorded as high in Pakistan ^[24]. According to the Antimicrobial Resistance Surveillance System (CARSS) and the China Antimicrobial Surveillance Network (CHINET), the antimicrobial resistance profiles of gram-negative bacilli are higher in China. There has been an increase in the incidence of carbapenem-resistant Klebsiella pneumoniae since 2005, and the prevalence of extended-spectrum-lactamases and antimicrobial resistance in Acinetobacter baumannii are both concerning. Furthermore, the incidence of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Pseudomonas aeruginosa both declined between 2005 and 2017 ^[25]. According to a report published by the European Antimicrobial Resistance Surveillance Network (EARS-Net), between 2015 and 2019, there were shifts in the frequency of antimicrobial resistance throughout the European Union. These changes were based on the species of bacteria, with E. coli being the most common (44.2%), followed by S. aureus (20.6%), K. pneumoniae (11.3%), Enterococcus faecalis (6.8%), P. aeruginosa (5.6%), Streptococcus pneumoniae (5.3%), E. faecium (4.5%), and Acinetobacter spp. (1.7%) ^[22]. Due to limited resources and the difficulty of monitoring medicine supply systems within and outside their borders, many African countries struggle to protect their populations from unsafe and substandard/counterfeit medicines. Several African countries have not yet banned oral artemisinin monotherapies for uncomplicated malaria, for example. This is a major risk for developing resistance to artemisinin-based combination therapies ^[26]. In all African regions, S. aureus, Klebsiella sp., E. coli, and S. pneumoniae exhibited lower resistance to carbapenems and fluoroquinolones than other antibiotic combinations. In West Africa, Klebsiella spp. resistance to ciprofloxacin was greater than in other regions ^[27]. In conclusion, antimicrobial resistance has emerged as a severe threat to human health in the last decades, responsible for an estimated 700,000 annual deaths worldwide; it is anticipated to result in millions of deaths by 2050 if not adequately addressed ^[28].