Editorial: The Global Threats of Increasing Antimicrobial Resistance Require New Approaches to Drug Development, Including Molecular Antimicrobial Adjuvants

In the past five years, while attention has focused on the COVID-19 pandemic and its consequences, antimicrobial resistance and the associated morbidity and mortality from untreatable common infectious organisms is an increasing threat to global public health [1,2]. Antimicrobial resistance impacts the prevention and treatment of infections caused by a growing range of bacteria, viruses, parasites, and fungi [3]. Due to media attention and focused public health alerts, there has been awareness of the rates of tuberculosis (TB) and multidrug-resistant TB (MDR TB) have recently increased, and new drug treatment combinations and molecular therapeutic approaches are in development [4,5].

In 2019, the Antimicrobial Resistance Collaborators published a study in the Lancet that involved 204 countries and included data from 471 million patient records to evaluate deaths directly due to and associated with antimicrobial resistance [6]. The Antimicrobial Resistance Collaborators were funded by the Wellcome Trust, the Bill and Melinda Gates Foundation, and the Department of Health and Social Care (DHSC) in the UK, with aid managed by the Fleming Fund [6]. Their study showed that antimicrobial resistance was directly responsible for up to 1.27 million deaths worldwide and was associated with 4.95 million deaths [6]. As a comparison, in 2019, HIV/AIDS and malaria caused 860,000 and 640,000 deaths, respectively [6]. This study also showed that antimicrobial resistance most severely affected low-income and middle-income countries [6]. However, in developed high-income countries, cases and mortality rates from antimicrobial resistance were also increasing at high levels [6]. Twenty-three different types of bacteria were studied, with drug resistance in six types of bacteria that contributed to 3.57 million deaths worldwide [6]. Also, up to 70% of deaths directly due to resistance to antibiotics were associated with previously reliable first-line antibiotics, including beta-lactams and fluoroquinolones [6]. Beta-lactam and fluoroquinolone antibiotics are commonly used to treat urinary tract infections (UTIs), upper respiratory tract infections (URTIs), pneumonia, and bone and joint infections [6]. The Antimicrobial Resistance Collaborators concluded that antimicrobial resistance could make common bacterial infections untreatable worldwide, and they estimated that this could result in 10 million deaths per year by 2050, overtaking cancer as a leading global cause of death [6]. Even in 2019, antimicrobial resistance was identified to be progressing more rapidly than previous estimates and highlighted that the world is running out of effective antibiotics, which means that common bacterial infections are becoming life-threatening again [3,6].

Annually, each November since 2016, the United Nations (UN) General Assembly has organized a week of meetings to promote awareness of the threats posed by antimicrobial resistance to human health, agriculture, and animal health [7]. At the November 2023 meeting, the UN also highlighted the increased loss of animal lives due to untreatable infections and identified that by the year 2050, livestock production could decline by up to 11% due to untreatable microbial infections [7]. The UN has also highlighted the economic effects, which are expected to result in a drop in GDP of at least $3.4 trillion each year by 2030, pushing 24 million more people into extreme poverty [7]. The UN General Assembly will meet again in September 2024 to consider antimicrobial resistance as part of a triple planetary crisis that also includes climate change, biodiversity loss, pollution, and the effects of extreme weather conditions [7]. On 9 May 2024, the World Bank, based in Washington, DC, published a framework for action to address antimicrobial resistance, which it highlighted as a global health and economic threat [8]. The World Bank has also clearly stated an intention to support governments with a World Bank Framework for Action to design interventions focusing on low-income and middle-income countries with 20 intervention areas across the health, water, and agriculture sectors [8].

There are several mechanisms for the development of antimicrobial resistance [9]. Because bacteria replicate rapidly, as part of our co-evolution, they develop mutations that give them a survival advantage in an environment of high antimicrobial use [9]. This situation is more likely to occur when antibiotic treatment is not completed, infection is not eradicated, or antibiotics are inappropriately used [9]. Also, antimicrobial resistance can be spread through the environment, including in the air, food, and drinking water, which may be contaminated by infected patients [9].

Many physical and chemical agents can damage the DNA of cells and microbes, including ultraviolet (UV) light, ionizing radiation, chemical alkylating and oxidizing agents, and cellular byproducts, such as reactive oxygen species (ROS) [10]. In 1974, Miroslav Radman introduced the term the SOS response for the induction of multiple proteins that promote the integrity of DNA and factors that allow for survival and replication even when DNA damage is present [11]. The SOS response repairs damaged DNA in bacteria and increases the rate of genetic mutations, which can accelerate the development of antibiotic resistance [10,11]. Because the SOS response is associated with increased mutagenesis, under normal physiological conditions, it requires complex regulation [10]. A potential molecular approach to controlling antibiotic resistance could be to develop an inhibitor of the mutagenic SOS response [10].

In June 2024, the findings of a study from researchers at the Ineos Oxford Institute for Antimicrobial Research (IOI) and the Oxford University Department of Pharmacology in the UK reported the use of a small molecule that can work alongside antibiotics to suppress the development of antimicrobial resistance in bacteria [12]. The authors studied a series of molecules previously reported to increase the sensitivity of methicillin-resistant Staphylococcus aureus (MRSA) to antibiotics and prevent the MRSA SOS response [12]. They modified the structure of different parts of the molecules and tested their actions against MRSA when given in combination with ciprofloxacin, a fluoroquinolone antibiotic [12]. The most potent SOS inhibitor molecule currently identified has been called OXF-077 [12]. When OXF-077 was combined with a range of antibiotics of different classes, treatment was more effective in preventing MRSA bacterial colony growth [12]. The authors tested the susceptibility and resistance of bacteria treated with ciprofloxacin with and without OXF-077 over a series of days to determine how quickly resistance to the antibiotic developed [12]. This study is the first to identify an inhibitor of the SOS response that can suppress the development of antibiotic resistance in bacteria [12]. A further finding was that when resistant bacteria previously exposed to ciprofloxacin were treated with OXF-077, the sensitivity to the antibiotic was restored to the same level as bacteria that had not developed resistance [12].

New antibiotics that have reached the market in an attempt to overcome antibiotic resistance have been compromised by the rapid emergence of resistant strains or by the selection of bacteria that harbor resistance to related antibiotics [13]. As a result, the pipeline of new antibiotics in clinical development has reached a point of last resort [3,13,14]. Therefore, developing new antimicrobial agents with novel mechanisms of action should also include compounds that can be partnered with existing antibiotics to block resistance mechanisms and enhance efficacy, such as beta-lactamase inhibitors [13]. Currently, an emerging target for developing adjuvants to antibiotics is the bacterial DNA-repair and SOS-response pathways [10,12]. This novel approach may control the upregulation of hypermutation, persistence of resistance, horizontal gene transfer, and bacterial [10,12].

Antimicrobial resistance should be recognized as a growing threat to global health and has the potential to cause even routine medical and surgical procedures too dangerous to be undertaken [15]. Realizing the severity, extent, and consequences of antimicrobial resistance supports the urgent need for new molecules that function through novel mechanisms of action [15]. Therefore, the rapid development of new antibiotics and antimicrobials, with new approaches that target infectious organisms at the molecular level, is urgently required [14,16]. The bacterial DNA repair and SOS-response pathways promote the survival of pathogens in human infections and activate hypermutation and resistance mechanisms [12,15]. Therefore, the bacterial DNA repair and SOS-response pathways are potential targets for new therapeutics [12,15]. Small molecules such as OXF-077 that are under investigation await future clinical development.

Conclusions

The relentless increase in antimicrobial resistance threatens global health, potentially making even routine medical and surgical procedures too dangerous. Realizing the severity, extent, and consequences of antimicrobial resistance supports the urgent need for new molecules that function through novel mechanisms of action, including molecular antimicrobial adjuvants that prevent the development of antimicrobial resistance.