Prospects for new antibacterials: can we do better?

Abstract

Bacterial resistance to antibacterial drugs has been increasing relentlessly over the past two decades. This includes common residents of the human body: Staphylococcus aureus (methicillin resistant or MRSA) Enteroccus faecalis and E. faecium (vancomycin resistant or VRE): Enterobacteriaceae (multiresistant, carbapenems included or CRE). It also includes environmental, opportunistic, but intrinsically multiresistant species: Pseudomonas aeruginosa and Acinetobacter baumannii. Financial considerations have curtailed R&D activity in the antibacterial field in all, but a couple of large pharmaceutical companies and small biotech companies have largely been unable to fill the drug discovery gap. Antibacterials currently under development have targeted, almost exclusively, Gram-positive bacteria; hence, greater effort must be directed against Gram-negative bacteria, particularly enterobacteria. There also has to be more transparency and care in clinical development. To get ahead of the problem of resistance, we must look for first-in-class antibacterials and new targets. The need to innovate is best addressed through partnerships between drug-makers and public institutions. Such partnerships would provide a long-term view and stability to projects, but also balance the interests of corporate and public stakeholders.

Keywords::

• antibacterial development
• carbapenem-resistant enterobacteria
• efflux pumps
• hospital-acquired infections
• inactivating enzymes
• multiresistant bacteria
• new antibacterials
• new targets

1. The making of a ‘perfect storm’

Resistance has been increasing relentlessly over the past two decades due to a constellation of factors: over-reliance on antibiotics for infection control and prevention in humans and farm animals; inappropriate use of antibacterials to treat viral infections; proliferation of vulnerable (aged, immunocompromised) patients; globalization (movement of people, goods and foodstuffs across the globe) [1-3]. Of great concern is also the worldwide emergence of drug-resistant tuberculosis, an infectious disease in a class by itself, as it affects a third of the world population (disproportionally poorer countries) and kills almost 10 million people annually [4,5].

The emerged and emerging bacterial resistance to established antibiotics should have been entirely predictable. The introduction of every single antibiotic, in human or veterinary medicine, has precipitated resistance – examples all of Darwinian adaptation. Nevertheless, the magnitude of antibacterial resistance, particularly in hospital-associated infections, over the past two decades has been staggering. It includes common residents of the human body that have acquired resistant targets or enzymes that inactivate the drugs: Staphylococcus aureus (methicillin resistant or MRSA [6]); Enteroccus faecalis and E. faecium (vancomycin resistant or VRE [7]): Enterobacteria (multiresistant, carbapenems included or CRE [8,9]). It also includes environmental, opportunistic, but intrinsically multiresistant species that thrive in hospital settings: Pseudomonas aeruginosa and Acinetobacter baumannii, both causing life-threatening infections in immunocompromised patents [9,10].

A related issue, stemming from the eradication of human intestinal microbiota by broad-spectrum antibiotics in hospitals, is the emergence of normally rare, but intrinsically antibiotic resistant and highly pathogenic species such as Clostridium difficile. This spore-forming anaerobe releases toxins that cause diarrhea and colitis which can be life-threatening [11]. Spore ingestion by hospital residents results in rapid dissemination throughout the institution. The emergence of hypervirulent C. difficile strains linked to antibiotic treatment in the past decade has called for the drastic – if inelegant – measure of fecal transplants [12].

Regrettably, financial considerations have curtailed R&D activity in the antibacterial field in all but a couple of the 20 large companies that were active two decades ago [13]. Antibacterials are typically used for days and are thus less profitable than drugs for chronic, lifetime conditions such as diabetes, cardiovascular disease, or cancer. In addition, companies must clear extra hurdles to bring a new antibacterial to market. This is because resistance to existing antibacterials puts a premium on first-in-class compounds, but their safety profile, probability of clinical success, and eventual approval depend to a large degree on existing knowledge which is lacking. In other therapeutic areas such as diabetes, cardiovascular disease, neurological disorders or even cancer, resistance is less of an issue and the premium is on best-in-class. This allows the effective harnessing of existing knowledge in clinical development and reduces risk.

Ironically, due again to antibiotic resistance, new antibacterials are also at risk of losing their effectiveness with widespread use and physicians tend to use them as second-line drugs, or even keep them in reserve to maintain their effectiveness [14]. Drugs for chronic conditions, on the other hand, may suffer from eventual patent loss and/or competition, but not from becoming wholesale ineffective with widespread use.

2. Antibacterial pipeline down to a trickle. Innovation and expertise too

Small Biotech companies have been largely unable to fill the drug discovery gap left by big Pharma's exit. The R&D inactivity has resulted in a drought for new antibacterials and a small number currently in development. The latter all belong to existing classes: lipoglycopeptides, cephalosporins, aminoglycosides, ketolides, oxazolidinones, antifolates [15]. Significantly, some (ketolides, oxazolidinones, lipoglycopeptides) have toxicity issues that preclude their systemic use in non-life threatening infections [16-18]. Alarmingly, antibacterials under development are targeting almost exclusively Gram-positive bacteria [19]. There is thus a desperate need for compounds active against Gram-negative bacteria, particularly enterobacteria resistant to currently available drugs, as well as for antibacterials that are better tolerated. A measure of the desperation is the proposed resurrection of polymyxin B, a toxic but effective agent, for resistant systemic infections [20].

Increased awareness of the skyrocketing resistance has promoted infection control, resistance surveillance, and antibiotic stewardship, all largely overlooked in the era of antibiotic abundance. Unfortunately, it has not reversed the chronic decline in antibacterial R&D or the parallel decline in expertise and innovation. The contrast with the flourishing oncology field is instructive. There, real investment has brought in real returns in recent years: impressive advances in companion diagnostics and minimally toxic treatments [21]. In the antibacterial field, we urgently need to move from awareness to change: reverse the decline in expertise and innovation and make the field sustainably fertile again.

Despite infection control measures, hospital-acquired infections (HAIs) in the United States alone cost close to USD 10 billion annually [22]. Antibacterials are therefore exceedingly cost effective: a two-week course, even with a new, high-priced antibacterial, costs orders of magnitude less than a year-long treatment with an antioncotic [23]. Hence, economics should not be an issue with new antibiotics. Premium prices for new, life-saving antibacterials are justified by treatment duration and proven effectiveness. Importantly, premium prices would ensure antibiotic stewardship.

3. Investing in antibacterial drug discovery

Short term, there has to be increased effort in rapid, point-of-care diagnostics so that the best drug is given to treat a patient's infection within hours. A correct diagnosis may permit the use of narrow-spectrum agents minimizing superinfections by resistant bacteria. It can also reduce the costs of clinical trials by identifying eligible patients. In addition, research on better diagnostic tools can help with resistance surveillance, recognizing emerging infections and patterns of resistance.

Greater effort must be directed against Gram-negative bacteria, particularly enterobacteria, where the outer membrane is almost always a contributing factor to resistance. Research should include efflux pumps that span both inner and outer membranes (as well as the intervening periplasm) and are key players in the development of drug resistance [24]. Antibiotic inactivating enzymes, particularly common in Gram-negative bacteria, should be targeted too, perhaps harnessing advances in biochemistry and genetics from other therapeutic areas.

Obviously, there has to be more transparency and care in clinical development. After telithromycin [25], regulators are naturally requiring more safety measures. Efficacy has to be balanced with toxicity, preferably in superiority trials rather than noninferiority ones. In this context, a recent article putting the onus of drugmakers' failure to come up with new anti-infectives on regulation would appear disingenuous [26].

4. Expert opinion

Ultimately, to get ahead of the problem of resistance, we must look for first-in class antibacterials and new targets, including resistance targets (efflux pumps, inactivating enzymes). This is perhaps the most difficult task requiring scientific research, genuine creativity, innovation and time. Since antibiotic development alone takes a decade [15], we need long-term research on: new, ‘druggable’ targets (most likely enzymes as the ribosome has proven too complicated to be a target for rational design); new compound classes, new antibiotic potentiators (targeting bacterial stress response perhaps), more narrow-spectrum drugs – the latter to be coupled with rapid diagnostics. Personalized anti-infectives, a concept borrowed from oncology, are worth considering.

Betting on antibacterial drug discovery is risky, hence the feast-or-famine nature of the business. However, the alternative is even riskier; all of the current best-selling antibacterials were approved over a decade ago. Innovation is essential. Unfortunately, bacterial innovation (resistance) is currently surpassing human innovation (new drugs). Perhaps nonprofits should take the lead in antibacterial drug discovery, as they can afford the long-term view. They should have input in development too as companies inevitably seek indications for new antibacterials that would increase sales volume, sometimes overlooking the efficacy–toxicity balance. Again, the story of telithromycin (and perhaps linezolid) is instructive.

The perennial question on how to innovate – productively, continuously and efficiently – is perhaps best addressed through partnerships between drug-makers and public institutions (universities, NIAID). Such partnerships would balance the interests of corporate and public stakeholders. The academic partner would lead in innovation and creativity, but also take the long view providing needed stability to the project. The corporate partner would provide translational input at an early stage so that innovations are harnessed expeditiously to produce antibacterials for unmet medical needs. The corporate partner would also contribute funds, scientific and technical knowledge, as well as expertise in clinical drug development and commercialization.

Key components to success will be long-term funding and value-sharing that preserves incentives. Also, ensuring that duplication/competition between partners is avoided and public funds are not invested for corporate profits. Such a development would be antithetical to what public funds were meant for, and would irreparably damage further partnerships. NIH/NAID must therefore take a proactive, oversight role to safeguard the public interest. If executed correctly, the proposed partnership would drastically increase the speed and efficiency of a new antibacterial reaching the market. As an added bonus, it would also increase infectious disease expertise in the public sector where there is a growing need.

Antibacterial drug discovery is a Sisyphean task, given the never-ending challenge of resistance. But there is no viable alternative.

Article highlights.

• Lack of new antibiotics, particularly against Gram-negative bacteria that dominate hospital-acquired infections.

• Antibiotics in development are all members of existing classes and act primarily against Gram-positive bacteria.

• Funding for research on new bacterial targets and bacterial resistance continues to decrease despite ‘calls to arms’; futile in the absence of ‘arms.’

• Long-term research efforts are needed on new, ‘druggable’ targets, new compound classes, new antibiotic potentiators; more narrow-spectrum drugs – the latter to be coupled with rapid diagnostics.

• The nature of bacterial resistance demands constant vigilance and innovation. The human and financial cost of complacency is staggering.

Declaration of interest

This author is an independent consultant with NHG Preclinical Research Consulting, LLC and has declared that she has no conflict of interest and received no payment in preparation of the manuscript.

Notes

This box summarizes key points contained in the article.