Open Access Review

Article DOI: 10.7759/cureus.46013

Antibiotic Resistance: Challenges and Strategies

in Combating Infections
Received 08/28/2023
Jay Chavada 1 , Komal N. Muneshwar 1 , Yash Ghulaxe 1 , Mohit Wani 1 , Prayas P. Sarda 1 , Shreyash Huse 1
Review began 09/01/2023
Review ended 09/13/2023 1. Department of Community Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education
Published 09/26/2023
and Research, Wardha, IND
© Copyright 2023
Chavada et al. This is an open access Corresponding author: Jay Chavada, [email protected]
article distributed under the terms of the
Creative Commons Attribution License CC-
BY 4.0., which permits unrestricted use,
distribution, and reproduction in any
medium, provided the original author and Abstract
source are credited.
From a broader perspective, antibiotic or antimicrobial resistance is still evolving and spreading
internationally. Infectious diseases have become more complex and often impossible to cure, increasing
morbidity and mortality. Despite the failure of conventional, standard antimicrobial therapy, no new class of
antibiotics has been developed in the last 20 years, which results in various cutting-edge and other tactics
that can be used to encounter these disease-causing microorganisms with antibiotic resistance. In the
continued fight against bacterial infections, there is an urgent requirement for new antibiotics and other
antimicrobials. Antibiotic resistance is inevitable, and pharmaceutical companies consistently show little
interest in funding novel antibiotic research. Some methods are being used as a possible replacement for
conventional antibiotics. Combination therapy, methods that target the proteins or enzymes that cause
antimicrobial resistance and bacterial resistance, systems for delivery of the drug, physicochemical
approaches, and informal ways, such as the CRISPR-Cas system, are some of these approaches. These
various approaches influence how multi-drug-resistant organisms are handled in human clinical settings.

Categories: Therapeutics
Keywords: enzyme inhibitor, antibiotic resistance, anti-microbial resistance, conventional antibiotics, combined
modality therapy

Introduction And Background

Antibiotics are used for both the prevention and cure of bacterial infections. Continuous use of antibiotics
makes bacteria resist, leading to antibiotic resistance (AR). A scenario when bacteria change and stop
responding to medication increases the risk of spread of disease, serious diseases, and death and makes
diseases challenging to treat [1]. When the capacity of bacteria to resist the outcome of antibiotics at
therapeutically feasible concentrations increases, it is referred to as bacterial resistance [2]. The growing
global issue known as AR is due to the lack of ability of medicine to manage the infectious diseases for
which they were designed. Now that the World Health Organization (WHO) has warned that the world is
"running out of antibiotics," and that the concerns about the rise of AR worldwide are intensifying. There has
recently been a significant challenge in treating clinical infectious disorders due to the growth of antibiotic-
resistant bacteria, which has led to a rise in the prevalence of nosocomial infections [3]. Because infections
due to bacteria are the leading causes of illness and mortality, AR is increasing worldwide. The recurring
emergence of new resistance mechanisms and their global dissemination threaten the ability to cure
common infectious diseases. Resistance to antibiotics is a severe healthcare problem due to its potential for
global spread, and limited treatment choices would arise [4]. Infections like pneumonia, TB, gonorrhea, and
food-borne disorders become more challenging; it is impossible to cure the disease when antibiotics are
ineffective. Infections due to bacteria are now dangerous, decades after the first patients got antibiotic
therapy. If prompt and proactive action is not taken, we are quickly moving into a post-antibiotic world in
which routine diseases and small wounds could be fatal again. AR was recently listed as one of the top 10
worldwide public health dangers to humanity by the WHO [1].

Review
Resistance to antibiotics and the rise in drug-resistant bacteria
Sir Alexander Fleming predicted the risks of incorrect penicillin usage and the onset of resistance in his
acceptance speech for the Nobel Prize in 1945 [5]. Antibiotics that are effective for treating general bacterial
infections, including sepsis, hospital-acquired infections, sexually transmitted infections, urinary tract
infections (UTI), and diarrhea, are becoming increasingly scarce globally [2]. The resistance rates for
Klebsiella pneumoniae and Escherichia coli to the antibiotic ciprofloxacin, which is frequently used to treat
UTI, were 8.4% to 92.9% and 4.1% to 79.4%, respectively, according to the WHO information sheet on
antimicrobial resistance [1]. Klebsiella pneumoniae can produce fatal infections, and carbapenem AR is an
issue affecting the entire world. The following factors all have an impact on the intricate and varied issue of
AR: a) Poor adherence to septic precautions and hospital etiquette, which contribute to a rise in AR in
bacteria, and excessive antibiotic usage in agriculture are two factors that contribute to the spread of
resistance. b) Rise in improper healthcare facility hygiene. c) Trade and international travel, which can cause

How to cite this article

Chavada J, Muneshwar K N, Ghulaxe Y, et al. (September 26, 2023) Antibiotic Resistance: Challenges and Strategies in Combating Infections.
Cureus 15(9): e46013. DOI 10.7759/cureus.46013
 the spreading of resistant germs. d) Poor sanitation in some locations can pollute water supplies and spread
bacteria that are resistant to treatment. e) A lack of fast diagnosis, among other things, prevents proper use
of antibiotics [6,7].

Bacterial resistance strategies against antibiotics

To flourish in the presence of an antibiotic, the bacterial strains must be able to try to hinder a few of the
crucial stages required for the antimicrobial drug to function well. Species of bacteria use any of four
fundamental survival techniques: a) Reducing the antibiotic's capacity to enter the microbial cell, preventing
it from reaching the antibiotic's target in the bacteria. b) The efflux pump mechanism helps the cell remove
antibacterial drugs. c) Modification or breakdown results in antibiotic deactivation. d) Modifying or altering
the bacteria's antibacterial target [8].

Epidemiology of AR
Around the world, AR is a leading reason of death and a financial burden. Incidences of several serious
multi-drug-resistant (MDR) bacterial infections have increased since 2013, according to the US Centers for
Disease Control and Prevention, including an erythromycin-resistant group A Streptococcus infection that
has increased by 315%, a drug-resistant Neisseria gonorrhoea infection that has increased by 124%, and an
extended-spectrum lactamase-producing Enterobacteriaceae infection that has increased by 50% [9].
Similarly, there was a 3.5% increase in the prevalence of resistance to vancomycin Streptococcus aureus
between 2006 and 2020, with Africa recording the most significant percentage (16%) [10]. According to a
WHO report, multi-drug-resistant tuberculosis (MDR-TB) has infected an estimated 3.3% of recent
tuberculosis (TB) cases and 18% of those already treated. A serious risk is the development of resistance to
recent "last resort" TB medications used for the treatment of drug-resistant TB. Low-income and middle-
income nations are highly affected because of widespread misuse of antibiotics, use of antibiotics in
agriculture, inappropriate drug quality, inadequate supervision, and some other factors linked to subpar
standards of health care, malnutrition, recurrent and chronic infections, and the lack of ability to afford
more potent and expensive medications [11].

Problems militating the development of new antibiotics

As existing medications and drug classes lose their efficacy, new drugs and drug classes must constantly be
developed to maintain the use of antibiotics in managing infectious diseases. The demand for novel anti-
infective medications in health care is immense, and time is rapidly exhausting. Although there is a
continued need for innovative antimicrobial medicines, high-yield pharmaceutical companies have dropped
this idea. The companies have moved out of the research and development of antibacterial drugs because of
the increased expenditure on clinical trials, advanced regulatory ambiguity around licensing needs, and a
low return [12,13]. This decline can be attributed to many factors, such as regulatory need that requires
lengthened and demanding clinical trials for validation of antibiotics as well as the low economic return in
financing for antibiotics in comparison to some different therapeutics, the difficulty of exploring newer
compounds using traditional discovery methods, the belief that resistance will arise with no doubt to new
antimicrobials, and other factors [14].

Emerging strategies for tackling AR

There is an urgent need for answers to the persistent danger of AR, as well as the associated risks, illness,
mortality, and economic losses. Despite the fact that many new antibiotics are now being created, according
to data published by the WHO, they are still anticipated to be effective in combating the most significant
forms of bacterial resistance against antibiotics [1].

Immune Antibiotics as an Alternative

Historically, antibiotics' direct repressing and killing effects are the only biological activities considered [15].
Contrarily, it is becoming more and more apparent that antimicrobials collaborate along the host's native
immunity to provide notable indirect effects that enhance the clearance of bacteria, which may result in
faster and more significant effects, reducing the likelihood of resistance emergence within residual bacteria
[15]. According to several findings, native endogenous host defense peptides have developed to save the host
by preventing pathogenic organisms from causing infection and have antimicrobial modes of action similar
to peptide antimicrobials administered to patients such as colistin and daptomycin [16]. Undoubtedly,
scientific study has been done on the synergistic, additive, neutralizing, and antagonistic effects of
antibiotics, but little is known about how antibiotics interact with the innate immune system [17,18].
Although an antibiotic's direct in vitro mode of action is believed to make it effective against bacteria, extra
antibiotic effects on the bacteria have been connected to improve immune optimization and host
immunological activities [19]. This incorporates how antibiotics work with other immune systems and
virulence factors to influence response to the host. In a study by Volk et al., it was found that patients with
methicillin-resistant Staphylococcus aureus (MRSA) bacteremia treated with lactam adjunctive therapy in
combination with both conventional antibiotics produced less IL-10 and more IL-1 as a result of the
influence of antibiotic responses on the immune system of the host [20]. Even while earlier attempts to
generate a Streptococcus aureus vaccine were unsuccessful, newly developed immunologic-based medicines

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 that incorporate anti-virulence factor antibodies with conventional medications seem to promise [21].

Biochemical Methods to Reduce Resistance and Increase Susceptibility to Currently Available Antibiotics

In recent years, scientists have started to concentrate their study on potential strategies for eliminating
bacteria that are resistant to antibiotics without necessarily developing new antibiotics. This strategy is
intriguing when considering the expense and difficulties of finding and developing new antibiotics. Each
kind of antibacterial antibiotic has a distinct mode of action that kills bacteria by attacking a particular
region of their cells. It is also widely believed that the physiological effects of the antibiotics, such as loss of
membrane permeability, alteration in the shape of the cell, or molecular events such as blockage of the key
cellular pathways, affect how these diverse kinds of antibiotics function and different ways of killing
bacteria [22]. After achieving their original targets, all antibiotic medications share a joint secondary impact,
according to research by Calhoun et al. and Hong et al. The target bacterium is reportedly forced to develop
"reactive oxygen species (ROS)," often referred to as free radicals, which, if not promptly neutralized, can
seriously harm the DNA of bacteria and proteins [23,24]. This suggests that all bactericidal antibiotics,
regardless of how they work, kill bacteria by having the same secondary impact on the bacterial cell. This
notion was previously supported by research and discoveries by Kohanski et al., who showed that when
tested against Gram-positive and Gram-negative bacteria, bactericidal drugs with different biological targets
caused the creation of ROS. On the other hand, bacteriostatic antibiotics did not result in the generation of
hydroxyl radicals; therefore, this was not the case [25]. Dual-acting immunoantibiotics, which target the
non-mevalonate or methyl-D-erythritol phosphate pathway of isoprenoid biosynthesis and the riboflavin
biosynthesis pathway in bacteria, have recently been presented (Figure 1) [26].

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 FIGURE 1: Mevalonate (MVA) methyl‐D‐erythritol phosphate (MEP)
pathway of isoprenoid biosynthesis in bacteria.
Source: [26]. This figure has been adapted from an open-source article distributed under the terms and conditions
of the Creative Commons Attribution NonCommercial 4.0 International (CC BY-NC 4.0) license
(https://creativecommons.org/licenses/by/4.0/).

A Crucial Stage in the Development of AR : The SOS Response

In reply to DNA damage and oxidative stress, the emergency response is known as an inducible repair of the
DNA pathway [27,28]. The growth of persister cells, stress resistance, and extended tolerance (including AR)
are all facilitated by the Salt Overly Sensitive (SOS) pathway, which is crucial for adapting bacteria,
pathogenicity, and diversification [29]. The SOS response was reportedly induced by antibiotic exposure, and
mutants of bacteria that are not able to produce clusters of iron-sulfur became less vulnerable to bactericidal
antibiotics, according to a study by Kohanski et al. [25]. This work also supports earlier findings that the SOS
response can be induced by antibiotics like ciprofloxacin and that it may play a vital role in the emergence of
drug resistance.

The Function of Hydrogen Sulfide (H2S) in Bacteria With Generalized AR

According to several studies, the synthesis of endogenous H2S by bacteria gives broad resistance to a
diversity of antibiotics, leading to antibiotics or resistance in almost all the bacteria examined so far [30,31].
A novel resistance pattern mediated by H2S was first discovered by Shatalin et al. in various clinical isolates
of Escherichia coli, Pseudomonas aeruginosa, Bacillus anthracis, and Streptococcus aureus [32]. According to
some reports, exogenous H2S may not have the same antibacterial properties as endogenous H2S. Exogenous
H2S is cytotoxic to various bacteria, including Acinetobacter baumannii and Escherichia coli, according to

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 findings [33]. Many clinical uses for various H2S-releasing compounds have been developed recently, and
their safety profiles have been described. Consideration of H2S-releasing chemicals becomes crucial to
enhance antibiotic effectiveness and reverse AR in bacteria that do not produce H2S [34]. According to some
reports, exogenous H2S may not have the same antibacterial properties as endogenous H2S. Exogenous H2S
is cytotoxic to a number of bacteria, including Escherichia coli and Acinetobacter baumannii, according to
research [35]. Similar findings were made by Podlesek and Bertok when researching the impact of exogenous
H2S on the essential antimicrobial-resistant bacterium Acinetobacter baumannii, which lacks the genes
necessary for H2S production. It was discovered that exogenous H2S was unsuccessful at shielding
Acinetobacter baumannii from antibiotics. Antibiotics such as colistin, gentamycin, clarithromycin, and
rifampicin, all of which are unrelated, were found to kill bacteria more effectively when H2S was present.
However, it was also found that the bactericidal activity of the medications was significantly more vigorous
when antibiotic-sensitive Acinetobacter baumannii were managed with H2S-releasing substances in addition
to antibiotics than when the antibiotics were administered alone. Many different clinical applications of
H2S-releasing molecules have been developed recently, and their safety profiles have been described.
Consideration of H2S-releasing chemicals becomes crucial for enhancing antibiotic effectiveness and
reversing AR in bacteria that cannot produce H2S [36].

Causes for concern

As is well known, H2S has both advantageous and detrimental effects on plants and animals. Surprisingly,
both effects are related to energy metabolism and either prevention from or exacerbation of oxidative
damage [37,38]. The third gasotransmitter in mammals like bears, after carbon monoxide and nitric oxide,
has been found, and it has been linked to a number of metabolic activities [39,40]. Cysteine is degraded by
the enzymes 3-mercaptopyruvate sulfurtransferase (3MST), cystathionine lyase (CSE), and cystathionine
synthase (CBS) in humans and microorganisms [41]. This suggests that human cells depend on H2S, which is
also produced by animal cells. In people, H2S acts as a signaling chemical, interacting with many organs,
including the smooth muscle and brain. However, it is highlighted that the H2S concentration range is the
main factor in determining the effect of H2S in an organism. Low levels of H2S are typically thought to be
cytoprotective, whereas large doses (millimolar) are thought to be cytotoxic [42]. Bacterial cells in humans
generate H2S via the CSE route. The tastes of bacterial and human CSE do, however, significantly vary.
Bacterial CSE, 3MST, and CBS have been found to differ substantially from their mammalian equivalents,
indicating the possibility of developing specialized inhibitors targeting these enzymes. Finding substances
with a substantial affinity for the bacterial CSE will help to ensure that they are both specifically effective
against bacteria and won't have any unintended negative impacts on the cells of mammals [43].

Conclusions
AR is still a serious issue that needs urgent global attention. The idea of the "one compound, one target"
approach, which has led to the development of antibacterial drugs, is effectively replaced by compounds or
techniques that obstruct critical metabolic pathways. Although accommodating, the analytical trials and
regulatory restrictions on this combinatorial approach to the discovery and advancement of antibiotics have
their limitations. The development of antibiotics is a promising technique for inhibiting germs and
enhancing the immune system. The various strategies that help in tackling AR have been implicated.
Additionally, antibiotic-induced reduction of the bacteria's other repair mechanisms may be the best defense
against bacterial infections.

Additional Information
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the
following: Payment/services info: All authors have declared that no financial support was received from
any organization for the submitted work. Financial relationships: All authors have declared that they have
no financial relationships at present or within the previous three years with any organizations that might
have an interest in the submitted work. Other relationships: All authors have declared that there are no
other relationships or activities that could appear to have influenced the submitted work.

References
1. Antimicrobial resistance. Accessed: August 24, 2023: https://www.who.int/health-topics/antimicrobial-
resistance.
2. Ranjbar R, Alam M: Antimicrobial Resistance Collaborators (2022). Global burden of bacterial antimicrobial
resistance in 2019: a systematic analysis. Evid Based Nurs. 2023, 10.1136/ebnurs-2022-103540
3. Zhu Y, Huang WE, Yang Q: Clinical perspective of antimicrobial resistance in bacteria . Infect Drug Resist.
2022, 15:735-46. 10.2147/IDR.S345574
4. Ugwu MC, Shariff M, Nnajide CM, Beri K, Okezie UM, Iroha IR, Esimone CO: Phenotypic and molecular
characterization of β-lactamases among enterobacterial uropathogens in Southeastern Nigeria. Can J Infect
Dis Med Microbiol. 2020, 2020:5843904. 10.1155/2020/5843904
5. Sir Alexander Fleming - Facts. NobelPrize.org. Nobel Prize Outreach AB 2023 . Accessed: September 25,
2023: https://www.nobelprize.org/prizes/medicine/1945/fleming/facts/.
6. Uddin TM, Chakraborty AJ, Khusro A, et al.: Antibiotic resistance in microbes: History, mechanisms,

2023 Chavada et al. Cureus 15(9): e46013. DOI 10.7759/cureus.46013 5 of 7

 therapeutic strategies and future prospects. J Infect Public Health. 2021, 14:1750-66.
10.1016/j.jiph.2021.10.020
7. Aworh MK, Kwaga JK, Hendriksen RS, Okolocha EC, Thakur S: Genetic relatedness of multidrug resistant
Escherichia coli isolated from humans, chickens and poultry environments. Antimicrob Resist Infect
Control. 2021, 10:58. 10.1186/s13756-021-00930-x
8. Peterson E, Kaur P: Antibiotic resistance mechanisms in bacteria: Relationships between resistance
determinants of antibiotic producers, environmental bacteria, and clinical pathogens. Front Microbiol.
2018, 9:2928. 10.3389/fmicb.2018.02928
9. Strathdee SA, Davies SC, Marcelin JR: Confronting antimicrobial resistance beyond the COVID-19 pandemic
and the 2020 US election. Lancet. 2020, 396:1050-3. 10.1016/S0140-6736(20)32063-8
10. Wu Q, Sabokroo N, Wang Y, Hashemian M, Karamollahi S, Kouhsari E: Systematic review and meta-analysis
of the epidemiology of vancomycin-resistance Staphylococcus aureus isolates. Antimicrob Resist Infect
Control. 2021, 10:101. 10.1186/s13756-021-00967-y
11. Md Haroon R, Rahman M, Sultana H, Islam K, Al Rakib MMN, Kalam MA, Efa SS: Antibacterial resistance
patterns of bacteria isolated from clinical specimens at Uttara IbnSina Diagnostic Centre, Dhaka. Afr J
Microbiol Res. 2020, 14:175-81. 10.5897/AJMR2020.9324
12. Dutescu IA, Hillier SA: Encouraging the development of new antibiotics: Are financial incentives the right
way forward? A systematic review and case study. Infect Drug Resist. 2021, 14:415-34. 10.2147/IDR.S287792
13. Tacconelli E, Carrara E, Savoldi A, et al.: Discovery, research, and development of new antibiotics: The WHO
priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis. 2018, 18:318-27.
10.1016/s1473-3099(17)30753-3
14. Ayukekbong JA, Ntemgwa M, Atabe AN: The threat of antimicrobial resistance in developing countries:
Causes and control strategies. Antimicrob Resist Infect Control. 2017, 6:47. 10.1186/s13756-017-0208-x
15. Berti A, Rose W, Nizet V, Sakoulas G: Antibiotics and innate immunity: A cooperative effort toward the
successful treatment of infections. Open Forum Infect Dis. 2020, 7:ofaa302. 10.1093/ofid/ofaa302
16. Rima M, Rima M, Fajloun Z, Sabatier JM, Bechinger B, Naas T: Antimicrobial peptides: A potent alternative
to antibiotics. Antibiotics (Basel). 2021, 10:1095. 10.3390/antibiotics10091095
17. Yeh PJ, Hegreness MJ, Aiden AP, Kishony R: Drug interactions and the evolution of antibiotic resistance . Nat
Rev Microbiol. 2009, 7:460-6. 10.1038/nrmicro2133
18. Tartor YH, Elmowalid GA, Hassan MN, Shaker A, Ashour DF, Saber T: Promising anti-biofilm agents and
phagocytes enhancers for the treatment of Candida albicans biofilm-associated infections. Front Cell Infect
Microbiol. 2022, 12:807218. 10.3389/fcimb.2022.807218
19. Watson K, Russell CD, Baillie JK, et al.: Developing novel host-based therapies targeting microbicidal
responses in macrophages and neutrophils to combat bacterial antimicrobial resistance. Front Immunol.
2020, 11:786. 10.3389/fimmu.2020.00786
20. Volk CF, Burgdorf S, Edwardson G, Nizet V, Sakoulas G, Rose WE: Interleukin (IL)-1β and IL-10 host
responses in patients with Staphylococcus aureus bacteremia determined by antimicrobial therapy. Clin
Infect Dis. 2020, 70:2634-40. 10.1093/cid/ciz686
21. Miller LS, Fowler VG, Shukla SK, Rose WE, Proctor RA: Development of a vaccine against Staphylococcus
aureus invasive infections: Evidence based on human immunity, genetics and bacterial evasion
mechanisms. FEMS Microbiol Rev. 2020, 44:123-53. 10.1093/femsre/fuz030
22. Lade H, Kim JS: Bacterial targets of antibiotics in methicillin-resistant Staphylococcus aureus . Antibiotics
(Basel). 2021, 10:398. 10.3390/antibiotics10040398
23. Patel P, Wermuth HR, Calhoun C, Hall GA: Antibiotics. StatPearls [Internet]. StatPearls Publishing, Treasure
Island, FL; 2023.
24. Hong Y, Zeng J, Wang X, Drlica K, Zhao X: Post-stress bacterial cell death mediated by reactive oxygen
species. Proc Natl Acad Sci U S A. 2019, 116:10064-71. 10.1073/pnas.1901730116
25. Kohanski MA, Dwyer DJ, Hayete B, Lawrence CA, Collins JJ: A common mechanism of cellular death induced
by bactericidal antibiotics. Cell. 2007, 130:797-810. 10.1016/j.cell.2007.06.049
26. Chinemerem Nwobodo D, Ugwu MC, Oliseloke Anie C, Al-Ouqaili MT, Chinedu Ikem J, Victor Chigozie U,
Saki M: Antibiotic resistance: The challenges and some emerging strategies for tackling a global menace . J
Clin Lab Anal. 2022, 36:e24655. 10.1002/jcla.24655
27. Blanchard L, de Groot A: Coexistence of SOS-dependent and SOS-independent regulation of DNA repair
genes in radiation-resistant Deinococcus bacteria. Cells. 2021, 10:924. 10.3390/cells10040924
28. Podlesek Z, Žgur Bertok D: The Escherichia coli SOS response: Much more than DNA damage repair .
Escherichia coli - Old and New Insights. Erjavec MS (ed): IntechOpen, London, England; 2021.
10.5772/intechopen.100353
29. Podlesek Z, Žgur Bertok D: The DNA damage inducible SOS response is a key player in the generation of
bacterial persister cells and population wide tolerance. Front Microbiol. 2020, 11:1785.
10.3389/fmicb.2020.01785
30. Mendes SS, Miranda V, Saraiva LM: Hydrogen sulfide and carbon monoxide tolerance in bacteria .
Antioxidants (Basel). 2021, 10:729. 10.3390/antiox10050729
31. Walsh BJ, Giedroc DP: H(2)S and reactive sulfur signaling at the host-bacterial pathogen interface . J Biol
Chem. 2020, 295:13150-68. 10.1074/jbc.REV120.011304
32. Shatalin K, Shatalina E, Mironov A, Nudler E: H2S: a universal defense against antibiotics in bacteria .
Science. 2011, 334:986-90. 10.1126/science.1209855
33. Fu LH, Wei ZZ, Hu KD, et al.: Hydrogen sulfide inhibits the growth of Escherichia coli through oxidative
damage. J Microbiol. 2018, 56:238-45. 10.1007/s12275-018-7537-1
34. Zaorska E, Tomasova L, Koszelewski D, Ostaszewski R, Ufnal M: Hydrogen sulfide in pharmacotherapy,
beyond the hydrogen sulfide-donors. Biomolecules. 2020, 10:323. 10.3390/biom10020323
35. Wen YD, Wang H, Zhu YZ: The drug developments of hydrogen sulfide on cardiovascular disease . Oxid Med
Cell Longev. 2018, 2018:4010395. 10.1155/2018/4010395
36. Wallace JL, Nagy P, Feener TD, et al.: A proof-of-concept, Phase 2 clinical trial of the gastrointestinal safety
of a hydrogen sulfide-releasing anti-inflammatory drug. Br J Pharmacol. 2020, 177:769-77.

2023 Chavada et al. Cureus 15(9): e46013. DOI 10.7759/cureus.46013 6 of 7

 10.1111/bph.14641
37. Aroca A, Gotor C, Bassham DC, Romero LC: Hydrogen sulfide: From a toxic molecule to a key molecule of
cell life. Antioxidants (Basel). 2020, 9:621. 10.3390/antiox9070621
38. Malone Rubright SL, Pearce LL, Peterson J: Environmental toxicology of hydrogen sulfide . Nitric Oxide.
2017, 71:1-13. 10.1016/j.niox.2017.09.011
39. Zhu Z, Chambers S, Zeng Y, Bhatia M: Gases in sepsis: Novel mediators and therapeutic targets . Int J Mol
Sci. 2022, 23:3669. 10.3390/ijms23073669
40. Giuffrè A, Vicente JB: Hydrogen sulfide biochemistry and interplay with other gaseous mediators in
mammalian physiology. Oxid Med Cell Longev. 2018, 2018:6290931. 10.1155/2018/6290931
41. Cao X, Ding L, Xie ZZ, Yang Y, Whiteman M, Moore PK, Bian JS: A review of hydrogen sulfide synthesis,
metabolism, and measurement: Is modulation of hydrogen sulfide a novel therapeutic for cancer?. Antioxid
Redox Signal. 2019, 31:1-38. 10.1089/ars.2017.7058
42. Pedre B, Dick TP: 3-Mercaptopyruvate sulfurtransferase: An enzyme at the crossroads of sulfane sulfur
trafficking. Biol Chem. 2021, 402:223-37. 10.1515/hsz-2020-0249
43. Ng SY, Ong KX, Surendran ST, et al.: Hydrogen sulfide sensitizes Acinetobacter baumannii to killing by
antibiotics. Front Microbiol. 2020, 11:1875. 10.3389/fmicb.2020.01875

2023 Chavada et al. Cureus 15(9): e46013. DOI 10.7759/cureus.46013 7 of 7